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MX2010009729A - Inhibitors of protein tyrosine kinase activity. - Google Patents

Inhibitors of protein tyrosine kinase activity.

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Publication number
MX2010009729A
MX2010009729A MX2010009729A MX2010009729A MX2010009729A MX 2010009729 A MX2010009729 A MX 2010009729A MX 2010009729 A MX2010009729 A MX 2010009729A MX 2010009729 A MX2010009729 A MX 2010009729A MX 2010009729 A MX2010009729 A MX 2010009729A
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optionally substituted
substituted
mmol
group
compound according
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MX2010009729A
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Spanish (es)
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Tetsuyuki Uno
Oscar Mario Saavedra
Lijie Zhan
Arkadii Vaisburg
Michael Mannion
Ljubomir Isakovic
Frederic Gaudette
Stephane Raeppel
Stephen William Claridge
Masashi Kishida
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Methylgene Inc
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Publication of MX2010009729A publication Critical patent/MX2010009729A/en

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Abstract

This invention relates to compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling. The invention also provides compounds, compositions and methods for treating cell proliferative diseases and conditions and opthalmological diseases, disorders and conditions.

Description

INHIBITORS OF PROTEIN ACTIVITY TYROSINE KINASE RELATED REQUESTS This application claims the benefit of the Provisional Application for E.U.A. Serial No. 61 / 034,005, filed March 5, 2008. All the teachings of the aforementioned application are incorporated herein for reference.
FIELD OF THE INVENTION This invention relates to compounds that inhibit protein tyrosine kinase activity. In particular, the invention relates to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, inhibition of VEGF receptor signaling and HGF receptor signaling. More particularly, the invention relates to compounds, compositions and methods for the inhibition of VEGF receptor signaling and HGF receptor signaling.
BACKGROUND OF THE INVENTION Tyrosine kinases can be classified as growth factor receptor (eg, EGFR, PDGFR, FGFR and erbB2) or non-receptor (eg c-src and bcr-abl) kinases. Receiver tyrosine kinases are composed of approximately 20 different subfamilies. Non-receptor type tyrosine kinases are composed of numerous families. These tyrosine kinases have different biological activity. Tyrosine kinase receptors are large enzymes that extend the cell membrane and possess an extracellular binding domain for growth factors, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate a specific tyrosine residue in proteins and by both to influence cell proliferation. Aberrant or inappropriate protein kinase activity may contribute to disease states associated with such aberrant kinase activity.
Angiogenesis is an important component of certain normal physiological processes such as embryogenesis and wound healing, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth. VEGF-A (vascular endothelial growth factor A) is a key factor that promotes neovascularization (angiogenesis) of tumors. VEGF induces endothelial cell proliferation and migration by means of signaling through two high affinity receptors, the fms-type tyrosine kinase receptor, Flt-1, and the receptor-containing kinase domain, KDR. These signaling responses are critically dependent on receptor dimerization and activation of intrinsic receptor tyrosine kinase (RTK) activity. The binding of VEGF as a disulfide-linked homodimer stimulates receptor dimerization and activation of the RTK domain. The kinase activity autophosphorylates the tyrosine residues of the cytoplasmic receptor, which then serves as binding sites for molecules involved in the propagation of a signaling cascade. ough multiple trajectories are linked to be clarified for both receptors, KDR signaling is studied more extensively, with a suggested mitogenic response to involve mitogen-activated protein kinases ERK-1 and ERK-2.
The interruption of VEGF receptor signaling is a very attractive therapeutic target in cancer, since angiogenesis is a prerequisite for all growth of solid tumors, and that mature endothelium remains relatively at rest (with the exception of female reproductive system and wound healing). Several experimental approaches to the inhibition of VEGF signaling have been examined, including the use of neutralizing antibodies, receptor antagonists, soluble receptors, antisense constructs and dominant-negative strategies.
Despite the attractiveness of anti-angiogenic therapy by inhibiting VEGF alone, several issues may limit this focus. The levels of VEGF expression can be elevated by numerous diverse stimuli and perhaps most importantly, the state of hypoxia of the tumors derived from the inhibition of VEGFR, can lead to the induction of factors that promote tumor invasion and metastasis. , the potential to undermine the impact of VEGF inhibitors as cancer therapies.
HGF (hepatocyte growth factor) and the HGF receptor, c-met, are involved in the ability of tumor cells to undermine the activity of VEGF inhibition. HGF derived from any of the stromal fibroblasts that surround tumor cells or expressed from the tumor itself have been suggested to play a pivotal role in tumor angiogenesis, invasion and metastasis. For example, the growth of invasive cancer cells is drastically improved by the interactions of the stromal tumor that affect the HGF / c-Met (HGF receptor) pathway. HGF, which was originally identified as a potent mitogen for hepatocytes is mainly secreted by stromal cells and secreted HGF can promote the motility and invasion of several cancer cells that express c-Met in a paracrine form. The binding of HGF to c-Met leads to phosphorylation of the receptor and activation of the Ras / mitogen-activated protein kinase signaling pathway (MAPK), thus improving the malignant behavior of cancer cells. On the other hand, stimulation of the HGF / c-met pathway itself can lead to the induction of VEGF expression, contributing automatically directly to the angiogenic activity.
Therefore, anti-angiogenic antitumor strategies or approaches that target VEGF / VEGFr signaling or HGF / c-met signaling may represent improved cancer therapies.
Tyrosine kinases also contribute to the pathology of ophthalmological diseases, diseases and conditions, such as age-related macular degeneration (AMD) and diabetic retinopathy (RD). The blindness of these diseases has been related to abnormalities in retinal neovascularization. The formation of new blood vessels is regulated by growth factors such as VEGF and HGF that activate tyrosine kinase receptors that result in the opening of signaling pathways that lead to the breakdown of plasma in the macula, causing vision loss. Kinases are attractive targets in this way for the treatment of ocular diseases involving neovascularization.
Therefore, there is a need to develop a strategy to control neovascularization of the eyes and develop a strategy for the treatment of eye diseases.
Small molecules that are potent inhibitors of tyrosine kinase protein activity are described below.
BRIEF DESCRIPTION OF THE INVENTION The present invention provides novel compounds and methods for the treatment of a disease sensitive to the inhibition of kinase activity, for example a disease sensitive to inhibition of protein tyrosine kinase activity, for example a disease sensitive to inhibition of kinase activity. the protein tyrosine kinase activity of the growth factor receptors, for example a disease sensitive to the inhibition of receptor tyrosine kinase signaling, or for example, a disease sensitive to the inhibition of VEGF receptor signaling. In one embodiment, the disease is a proliferating cell disease. In another modality, the disease is an ophthalmological disease. The compounds of the invention are inhibitors of kinase activity, such as protein tyrosine kinase activity, for example protein tyrosine kinase activity of growth factor receptors, or for example receptor tyrosine kinase signaling.
In a first aspect, the invention provides compounds of formula (I) that are useful as kinase inhibitors: and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and their complexes, and racemic and scala mixtures, diastereomers and enantiomers thereof, wherein D, M, Z, Ar and G are as defined herein. Because the compounds of the present invention are useful as kinase inhibitors, they are, therefore, useful research tools for studying the role of kinases in normal and disease states. In some embodiments, the invention provides compounds that are useful as inhibitors of VEGF receptor signaling and, therefore, are useful research tools for the study of VEGF function in normal and disease states.
The reference to "a compound of the formula (I)", (or equivalently, "a compound according to the first aspect", or "a compound of the present invention", and the like), hereinafter will be understood to include reference to N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and their complexes, and racemic and scala mixtures, diastereomers, enantiomers and tautomers thereof, unless otherwise indicated.
In a second aspect, the invention provides compositions comprising a compound according to the present invention and a pharmaceutically acceptable carrier, excipient or diluent. For example, the invention provides compositions comprising a compound that is an inhibitor of VEGF receptor signaling, or a pharmaceutically acceptable salt thereof, and a carrier pharmaceutically acceptable, excipient or diluent.
In a third aspect, the invention provides a method of inhibiting kinase activity, for example protein tyrosine kinase, for example the activity of the tyrosine kinase of a growth factor receptor, including the contact method of the kinase with a compound according to the present invention, or with a composition according to the present invention. In some embodiments of this aspect, the invention provides a method of inhibiting tyrosine kinase receptor signaling, eg, inhibition of VEGF receptor signaling. The inhibition can be in a cell or a multicellular organism. If in a cell, the method according to this aspect of the invention comprises contacting the cell with a compound according to the present invention, or with a composition according to the present invention. If in a multicellular organism, the method according to this aspect of the invention comprises administering to the organism a compound according to the present invention, or a composition according to the present invention. In some embodiments the organism is a mammal, for example a primate, for example, a human being.
In a fourth aspect, the invention provides a method of inhibiting angiogenesis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, or a therapeutically effective amount of a composition according to the present invention.
In some embodiments of this aspect, the angiogenesis that must be inhibited is involved in the growth of the tumor. In some other forms of angiogenesis modality that will be inhibited is retinal angiogenesis. In some embodiments of this aspect, the patient is a mammal, for example a primate, for example, a human being.
In a fifth aspect, the invention provides a method for treating a disease sensitive to the inhibition of kinase activity, for example a disease sensitive to the inhibition of tyrosine kinase protein activity, for example a disease sensitive to the inhibition of protein activity. Thiosin kinase from growth factor receptors. In some embodiments of this aspect, the invention provides a method for treating a disease sensitive to inhibition of receptor tyrosine kinase signaling., for example a disease sensitive to inhibition of VEGF receptor signaling, the method comprising administering to an organism in need thereof a therapeutically effective amount of a compound according to the present invention, or a composition according to the present invention. In some embodiments of this aspect, the organism is a mammal, for example a primate, for example, a human being.
In a sixth aspect, the invention provides a method for treating a cell proliferative disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, or a therapeutically effective amount of a composition. according to the present invention. In some embodiments of this aspect, the cell proliferation disease is cancer. In some embodiments, the patient is a mammal, for example a primate, for example, a human being.
In a seventh aspect, the invention provides a method for treating an ophthalmic disease, disorder or disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, or a therapeutically effective amount of a composition according to the present invention. In some modalities of this aspect, the disease is caused by choroidal angiogenesis. In some embodiments of this aspect, the patient is a mammal, for example a primate, for example, a human being.
In an eighth aspect, the invention provides the use of a compound according to the present invention for or in the manufacture of a medicament for inhibiting kinase activity, for example, to inhibit protein tyrosine kinase activity, for example, to inhibit the protein tyrosine kinase activity of growth factor receptors. In some embodiments of this aspect, the invention provides the use of a compound according to the present invention for or in the manufacture of a medicament for inhibiting receptor tyrosine kinase signaling, for example, to inhibit receptor signaling. VEFG. In some embodiments of this aspect, the invention provides the use of a compound according to the present invention for or in the manufacture of a medicament for treating a disease responsive to inhibition of kinase activity. In some embodiments of this aspect, the disease is sensitive to the inhibition of tyrosine kinase protein activity, for example the inhibition of protein tyrosine kinase activity of growth factor receptors In some embodiments of this aspect, the disease is sensitive to inhibition of receptor tyrosine kinase signaling, for example the signaling of the VEGF receiver. In some embodiments, the disease is a cell proliferating disease, for example, cancer. In some embodiments of this aspect, the disease is an ophthalmic disease, disorder or condition. In some embodiments of this aspect, the ophthalmic disease, disorder or condition is caused by choroidal angiogenesis. In some modalities of this aspect, the disease is age-related macular degeneration, diabetic retinopathy or retinal edema.
In a ninth aspect, the invention provides the use of a compound according to the present invention, or a composition thereof, to inhibit kinase activity, for example, to inhibit receptor tyrosine kinase-like activity, for example, to inhibit protein tyrosine kinase activity of growth factor receptors. In some embodiments of this aspect, the invention provides the use of a compound according to the present invention, or a composition thereof, to inhibit tyrosine kinase receptor signaling, for example, to inhibit VEGF receptor signaling.
In a tenth aspect, the invention provides the use of a compound according to the present invention, or a composition thereof, for treating a disease sensitive to inhibition of kinase activity, for example a disease sensitive to activity inhibition. of protein tyrosine kinase, for example a disease sensitive to inhibition or protein tyrosine kinase activity of the growth factor receptor. In some modalities of this aspect, the invention provides the use of a compound according to the present invention, or a composition thereof, to treat a disease sensitive to the inhibition of receptor tyrosine kinase signaling, for example a disease sensitive to signaling inhibition of the receptor. VEGF. In some embodiments of this aspect, the disease is a cell proliferating disease, for example cancer. In some embodiments of this aspect, the disease is a disease, disorder or ophthalmic condition. In some embodiments of this aspect, the disease, disorder or ophthalmic condition is caused by choroidal angiogenesis.
The foregoing is limited to summarizing some aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and modalities are described in more detail below.
DETAILED DESCRIPTION OF THE INVENTION The invention provides compounds, compositions and methods for inhibiting kinase activity, for example, protein tyrosine kinase activity, for example, the activity of the protein kinase receptor, for example, the KDR receptor of VEGF. The invention also provides compounds, compositions and methods for inhibiting angiogenesis, the treatment of a disease responsive to inhibition of kinase activity, treatment of cell proliferation diseases and the conditions and treatment of diseases, disorders and ophthalmic conditions. The patent and the scientific literature referred to here reflect the knowledge that is available to those with knowledge in the field. The granted patents, published patent applications and the references cited in this document are incorporated by reference to the same extent as if each is specific and individually indicated to be incorporated by reference. In the case of inconsistencies, the present description will prevail.
For the purposes of the present invention, the following definitions will be used (unless expressly stated otherwise): For simplicity, chemical radicals are defined and referred to throughout the description primarily as univalent chemical radicals (eg, alkyl, aryl, etc.). However, such terms are also used to transmit corresponding multivalent radicals under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" radical generally refers to a monovalent radical (eg, CH3-CH2-), under certain circumstances, a bivalent linking radical may be "alkyl", in which case those skilled in the art will understand the alkyl as a divalent radical (for example, -CH2-CH2-), which is equivalent to the term "alkylene". In the same way, in circumstances where a divalent radical is required and it is affirmed as "aryl", those skilled in the art will understand that the term "aryl" refers to the corresponding divalent radical, arylene. All atoms are understood to have their normal number of valences for bond formation (ie, 4 for carbon, 3 for N, 2 for O, and 2, 4 or 6 for S, depending on the oxidation state of S). ). Sometimes a radical can be defined, for example, as (A) a-B-, where a is 0 or 1. In these cases, when a is 0 the radical is B and when a is 1 the radical is A-B-.
For simplicity, the reference to a heterocyclyl "Cn-Cm" or "Cn-Cm" heteroaryl means a heterocyclyl or heteroaryl having "n" to "m" ring atoms, where "n" and "m" are integers . Thus, for example, a C5-C6heterocyclyl is a 5- or 6- membered ring with at least one heteroatom, and includes pyrrolidinyl (C5) and piperazinyl and piperidinyl (C6). Ceheteroaryl includes, for example, pyridyl and pyrimidyl.
The term "hydrocarbyl" refers to a straight or branched alkyl, alkenyl, or alkynyl each as defined herein. One co" Hydrocarbyl is used to refer to a covalent bond. Thus, "C0-C3 hydrocarbyl" includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl and cyclopropyl.
The term "alkyl" designates a straight or branched chain aliphatic group having from 1 to 12 carbon atoms, alternatively 1 -8 carbon atoms, and, alternatively, 1-6 carbon atoms. In some embodiments, the alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms and alternatively 2-6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tere-butyl, pentyl, hexyl, and the like. A "C0" alkyl (as in "C0-C3alkyl") is a covalent bond.
The term "alkenyl" is intended to refer to an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, with 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively, 2- 6 carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl and hexenyl.
The term "alkynyl" is intended to refer to an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, with 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively, 2- 6 carbon atoms. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
The terms "alkylene", "alkenylene", or "alkynylene" as used herein are intended to mean an alkyl, alkenyl, alkynyl group, respectively, as defined herein above, which is placed between and serves to connect two chemical groups . Examples of alkylene groups include, without limitation, methylene, ethylene, propylene and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
The term "carbocycle" as used herein means a cycloalkyl or aryl radical.
The term "cycloalkyl" designates a mono-, bi-, tri- or polycyclic, unsaturated or partially unsaturated, saturated hydrocarbon group having about 3 to 15 carbon atoms, alternatively having 3 to 12 carbon atoms, alternatively 3 to 8 carbon atoms, alternatively 3 to 6 carbon atoms, and alternatively 5 or 6 carbon atoms. In some embodiments, the cycloalkyl group is fused with an aryl, heteroaryl or heterocyclic group. Examples of cycloalkyl groups include, without limitation, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl. , etc.
The term "heteroalkyl" is intended to mean a straight or branched chain, saturated, partially unsaturated, or unsaturated aliphatic group, wherein one or more carbon atoms in the group are replaced by a heteroatom selected from the group consisting of O, S, and N.
The term "aryl" is intended to designate a mono, bi, tri or polycyclic aromatic radical having one to three aromatic rings. In some embodiments the aryl is an aromatic C6-C14 radical, alternatively the aryl group is a C6-C10 group, alternatively an aryl Ce group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl and fluorenyl.
The terms "aralkyl" or "arylalkyl" are intended to refer to a group consisting of an aryl group covalently linked to an alkyl group. If an aralkyl group is described as "optionally substituted", it is intended that either or both aryl and alkyl radicals independently may be optionally substituted or unsubstituted. In some embodiments, the aralkyl group is (CrC6) alc (C6-C10) aryl, including, without limitation, benzyl, phenethyl and naphthylmethyl. For simplicity, when this term is written as "arylalkyl", and terms related thereto, it is intended to indicate the order of the groups in a compound such as "aryl-alkyl". Similarly, "alkyl-aryl" is intended to indicate the order of the groups in a compound such as "alkyl-aryl".
The terms "heterocyclyl", "heterocyclic" or "heterocycle" are intended to refer to a group that is a mono-, bi-, or polycyclic structure having from 3 to about 14 atoms, alternatively 3 to 8 atoms, alternatively 4 to 7 atoms, alternatively 5 or 6 atoms wherein one or more atoms, for example 1 or 2 atoms, are selected independently of the group consisting of N, O and S, the rest of the atoms that make up the ring are carbon atoms. The ring structure can be saturated, unsaturated or partially unsaturated. In some embodiments, the heterocyclic group is non-aromatic, in which case the group is also known as a heterocycloalkyl. In a bicyclic or polycyclic structure, one or more rings may be aromatic; for example, a ring of a bicyclic heterocycle or one or two rings of a tricyclic heterocycle may be aromatic, as in indane and 9,10-dihydro anthracene. Examples of heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, morpholino, thienyl, pyridyl, 1,2-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazino, piperidyl, piperidino, morpholinyl, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl and azepanyl. In some embodiments, the heterocyclic group is fused with an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the field of this term are compounds where an O or S ring atom is adjacent to another O or S atom.
In some embodiments, the heterocyclic group is a heteroaryl group. As used herein, the term "heteroaryl" is intended to designate a mono-, bi-, tri or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9 or 10 ring atoms; having, for example, 6, 10, or 14 pi electrons shared in a cyclic array, and having, in addition to carbon atoms, between one or more heteroatoms independently selected from the group consisting of N, O, and S. For example, a heteroaryl group include, without limitation, pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl. Other examples of heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl and isoxazolyl.
The terms "arylene", "heteroarylene", or "heterocyclylene" mean an aryl, heteroaryl, or a heterocyclyl group, respectively, as defined herein above, which is placed between and serves to connect two other chemical groups.
Examples of heterocyclyls and heteroaryls include, but are not limited to, azepinyl, azetidinyl, acridinyl, azocinyl, benzidolyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzthriazolyl, benzitetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzoxazolyl, benzoxadiazolyl, benzopyranyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, coumarinyl, decahydroquinolinyl, 1,3-dioxolane, 2H, 6H-1, 5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), furanyl, furopyridinyl (such as fuor [2,3-c] pyridinyl, furo [3,2-b] pyridinyl or furo [2,3-b] pyridinyl), furyl, furazanyl, hexahydrodiazepinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, 1 H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolinyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3- oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxythinyl, phenoxyazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridin doimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolopyridyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro-1,1-dioxotienyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrazolyl, thiazolidinyl, 6H-1, 2,5-thiadiazinyl, thiadiazolyl (for example 1,2,3-thiadiazolyl, 1,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4 thiadiazolyl), thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholyl sulfone, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazinilazepinyl, triazolyl (for example 1,2,3-triazolyl, 1,2,4-triazolyl) , 1, 2,5-triazolyl, 1,4-triazolyl), and xanthenyl.
The term "azolyl" as used herein is intended to mean a saturated or unsaturated five-membered heterocyclic group containing two or more heteroatoms, such as ring atoms, selected from the group consisting of nitrogen, sulfur and oxygen, wherein at least one of the heteroatoms is a nitrogen atom. Examples of azolyl groups include, but are not limited to, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,4-thiadiazolyl, 1,4-oxadiazolyl, and , Optionally substituted 3,4-oxadiazolyl.
As used herein, and unless otherwise indicated, when a moiety (eg, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) is described as "optionally substituted" it is understood that the group optionally alternatively one or two alternatively selected non-hydrogen substituents are selected from one to four, alternatively from one to three. Suitable substituents include, without limitation, halo, hydroxy, oxo (for example, a -CH-substituted ring with oxo is -C (O) -) nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, arenesulfonyl, alkanesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano and ureido groups.
Examples of substituents, which in turn are not further substituted (unless expressly stated otherwise) are the following: (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, (b) CrC5alkyl or alkenyl or arylalkyl, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, Cr C8alkyl, Ci-C8alquenilo, C C8alcoxi, CrCsalquiamino, d-C8alcoxicarbonilo, aryloxycarbonyl, C2-C8acilo, C2-C8acilamino, CrCealquiltio, arylalkylthio, arylthio, Ci-C8alquilsulfinilo, arylalkylsulfinyl, arylsulfinyl, d-C8alquilsulfonilo, arylalkylsulfonyl, arylsulfonyl, C0-C6 / V-alkyl carbamoyl, C2-C15 / /, / V-dialkylcarbamoyl, C3-C7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or other aryl ring, C3-C7heterocycle, C5- C-heteroaryl or any of these ring fused or spiro-fumes to a cycloalkyl, heterocyclyl, or aryl, wherein each of the above is optionally substituted with one or more radicals listed in (a), above; Y (c) (CR32R33) S-NR30R31, where s is 0 (case in which nitrogen is directly linked to the radical that is replaced) to 6, R32 and R33 each independently is hydrogen, halo, hydroxyl or Ci-C4alkyl, and R30 and R31 each independently is hydrogen, cyano, oxo, hydroxyl, Ci-C8alkyl, Ci-C8heteroalkyl, d-C8alkenyl, carboxamido, CrC3alkylcarboxamido , carboxamido-Cr C3alkyl, amidino, C2-C8hydroxyalkyl, CrC3alkylaryl, aryl-Ci-C3alkyl, C C3alkylheteroaryl, heteroaryl-Ci-C3alkyl, CrCalkalkheheterocyclyl, heterocyclic-Ci-C3alkyl CrCalkylcycloalkyl, cycloalkyl-Ci-C3alkyl, C2-C8alkoxy, C2-C8alkoxy-CrC4alkyl, Ci-C8alkoxycarbonyl, aryloxycarbonyl, aryl -CrC3alkoxycarbonyl, heteroaryloxycarbonyl, heteroaryl-C1-C3alkoxycarbonyl, C8-acyl, C0-C8alkylcarbonyl, aryl-C0-C8alkylcarbonyl, heteroaryl-Co-C8alkylcarbonyl, cycloalkyl-C0-C8alkylcarbonyl, Co-C8alkyl-NH- carbonyl, aryl-Co-C8alkyl-NH-carbonyl, heteroaryl-Co-Csalkyl-NH-carbonyl, cycloalkyl-C0-C8alkyl-NH-carbonyl, C0-C8alkyl-O-carbonyl, aryl-C0-C8alkyl-O-carbonyl, heteroaryl-C0-C8alkyl-O-carbonyl, cycloalkyl-C0-C8alkyl-O-carbonyl, d-Csalkylsu! fonyl, arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl, heteroarylsulphonyl, C8alkyl-NH-sulfonyl, arylalkyl-NH-sulfonyl, aryl-NH -sulfonyl, heteroarylalkyl-NH-sulfonyl, heteroaryl-NH-sulfonyl-aroyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C-C3al quil-, C3-alkylcycloalkyl-, heterocyclyl-CrCalkyl-, heteroaryl-C-C3alkyl-, or protecting group, wherein each of the above is optionally further substituted with one or more radicals listed in (a), above; or R30 and R31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of (a) above, a protecting group, and (X30- Y31-), wherein said heterocyclyl can also be bridged (forming a bicyclic radical with a methylene, ethylene or propylene bridge); where X is selected from the group consisting of CrC8alkyl, C2-C8alkenyl-, C2-C8alkynyl-, -Co-C3alkyl-C2-C8alkenyl-Co-C3alkyl, C0-C3alkyl-C2-C8alkynyl-Co-C3alkyl, Co-C3alkyl-0 -C0-C3alkyl-, HO-C0-C3alkyl-, C0-C4alkyl-N (R30) -Co-C3alkyl-, N (R30) (R31) -C0-C3alkyl-, N (R30) (R31) -C0- C3alkenyl-, N (R30) (R3) -C0-C3alkynyl-, (N (R30) (R31)) 2-C = N-, Co-C3alkyl (O) o.2-Co-C3alkyl-, CF3 -C0-C3alkyl-, CrChesheteroalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-Ci-C3alkyl-, cycloalkyl-d-C3alkyl-, heterocyclyl-Ci-C3alkyl-, heteroaryl-CrC3alkyl-, N (R30) (R31) ) -heterocyclyl-CrC3alkyl-, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with 1 to 3 substituents of (a); Y Y31 is selected from the group consisting of a direct bond, -O-, -N (R30) -, -C (O) -, -OC (O) -, -C (0) -0-, -N (R30 ) -C (O) -, -C (0) -N (R30) -, -N (R30) -C (S) -, -C (S) -N (R30) -, -N (R30) - C (O) -N (R31) -, -N (R30) -C (NR30) -N (R31) -, -N (R30) -C (NR31) -, -C (NR3) -N (R30) -, -N (R30) -C (S) -N (R31) -, -N (R30) -C (O) -O-, -0-C (0) -N (R31) -, -N ( R30) -C (S) -O-, -0-C (S) -N (R31) -, -S (O) 0.2-, -S02N (R31) -, -N (R31) -S02- and - N (R30) -SO2N (R31) -.
A radical that is substituted is one in which one or more (for example one up to four, alternatively from one to three and alternatively, one or two), hydrogens have been replaced independently with another chemical substituent. By way of non-limiting example, substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl-, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl.
Included within this definition are methylenes (-CH2-) substituted with oxygen to form carbonyl -CO-.
When there are two optional substituents attached to adjacent atoms of a ring structure, such as, for example, a phenyl, thiophenyl or pyridinyl, the substituents, together with the atoms to which they are attached, optionally form a 5 or 6 membered cycloalkyl or heterocycle having 1, 2, or 3 ring heteroatoms.
In some embodiments, a hydrocarbyl, heteroalkyl, heterocyclic and / or aryl group is unsubstituted.
In some embodiments, a hydrocarbyl, heteroalkyl, heterocyclic and / or an aryl group is substituted by 1 to 3 independently selected substituents.
Examples of substituents on the alkyl groups include, but are not limited to, hydroxyl, halogen (for example, an individual halogen substituent or multiple halo substituents, in the latter case, groups such as CF3 or an alkyl group having Cl3), oxo, cyano, nitro, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, -ORa, -SRa, -S (= 0) Re, -S (= 0) 2Re, -P (= 0) 2Re, -S (= O) 2ORe, -P (= O) 2ORe, -NRbRc, - NRbS (= 0) 2Re , -NRbP (= 0) 2Re, -S (= 0) 2NRbRc, -P (= 0) 2NRbRc, -C (= 0) ORe, -C (= O) Ra, -C (= O) NR Rc, -OC (= 0) Ra, -OC (= 0) NRbRc, -NRbC (= O) ORe, - NRdC (= 0) NRbRc, -NRdS (= 0) 2NRbRc, -NRdP (= 0) 2NRbRc, -NRbC (= 0) Ra or -NRbP (= 0) 2 Re, wherein Ra is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; Rb, Rc and Rd are independently hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or said Rb and R ° together with the N to which they are attached optionally form a heterocycle; and Re is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can be optionally substituted by themselves Examples of substituents on the alkenyl and alkynyl groups include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited as examples of the alkyl substituents.
Examples of the substituents on the cycloalkyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as the groups recited above as examples of the alkyl substituents. Other examples of the substituents include, but are not limited to fused spiro-linked or cyclic substituents, for example, spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkenyl, fused cycloalkyl, fused heterocycle, or fused aryl, wherein the above-mentioned substituents cycloalkyl, cycloalkenyl, heterocycle and aryl may be optionally substituted by themselves.
Examples of substituents on the cycloalkenyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited as examples of the alkyl substituents. Other examples of substituents include, but are not limited to, spiro-linked cyclic substituents. or fused, for example spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the above-mentioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may be themselves optionally substituted.
Examples of substituents on the aryl groups include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groups recited above as an example of the alkyl substituents. Other examples of substituents include, but are not limited to, fused cyclic groups, such as fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the aforementioned cycloalkyl, cylcoalkenyl, heterocycle, and aryl substituents may be optionally substituted automatically. Still other examples of the substituents on the aryl groups (phenyl, as a non-limiting example) include, but are not limited to, haloalkyl and those groups recited as examples of the alkyl substituents.
Examples of substituents on the heterocyclic groups include, but are not limited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, nitro, oxo (i.e., = 0), cyano, alkyl, substituted alkyl, as well as those groups recited as examples of alkyl substituents. Other examples of substituents in the groups heterocyclics include, but are not limited to, spiro-linked cyclic substituents or fused at any available point or junction points, for example spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, cycloalkenyl, fused heterocycle and fused aryl, wherein the above-mentioned substituents cycloalkyl, cycloalkenyl, heterocycle and aryl can optionally be replaced by themselves.
In some embodiments, a heterocyclic group is substituted at carbon, nitrogen and / or sulfur at one or more positions. Examples of substituents on nitrogen, but not limited to alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Examples of substituents on sulfur include, but are not limited to, oxo and C 1-6 alkyl. In some embodiments, nitrogen and sulfur heteroatoms independently can optionally be oxidized and nitrogen heteroatoms independently can optionally be quaternized.
In some embodiments, substituents on the ring groups, such as aryl, heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy and / or alkyl.
In some embodiments, the substituents on the alkyl groups are halogen and / or hydroxy.
A "halohydrocarbyl" as used herein is a hydrocarbyl radical, wherein one of all the hydrogens has been replaced with one or more halo.
The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, or iodine. As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acylamino" refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group attached to the carbonyl carbon atom (ie, NH2-CO-). The nitrogen atom of an acylamino or carbamoyl substituent is, in addition, optionally substituted. The term "sulfonamido" refers to a sulfonamido substituent attached either by the sulfur or the nitrogen atom. The term "amino" is intended to include NH 2, alkylamino, dialkylamino (where each alkyl may be the same or different), arylamino, and cyclic amino groups. The term "ureido" as used herein refers to a substituted or unsubstituted ureido radical.
The term "radical" as used herein means a chemical radical comprising one or more unpaired electrons.
When optional substituents are chosen from "one or several" groups it should be understood that this definition includes all substituents that are chosen within one of the specified groups or from the combination of all specified groups.
In addition, substituents on cyclic radicals (ie, cycloalkyl, heterocyclyl, aryl, heteroaryl) include mono-5- to 6-member radicals and 9- to 14-bi-cyclic members fused to the cyclic radical of origin to form a ring system fused bi- or tri-cyclic. The Substituents on cyclic radicals also include mono-5- to 6-member radicals and 9- to 14-bi-cyclic members linked to the cyclic radical of origin by means of a covalent bond to form a bi- or tricyclic abi-ring system. For example, an optionally substituted phenyl includes, but is not limited to, the following: An "unsubstituted" radical (eg, unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means a radical as defined above that does not have any type of optional substituents.
A partially unsaturated or unsaturated carbocyclic ring of three to eight members is for example a saturated or unsaturated carbocyclic ring, of five to six members. Examples of three to eight membered saturated or unsaturated carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
A saturated or unsaturated carboxylic and heterocyclic group can be condensed with another heterocyclic or saturated group to form a bicyclic group, for example a carbocyclic or heterocyclic, bicyclic group of nine to twelve members, saturated or unsaturated. The bicyclic groups include naphthyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, 1,4-benzoxanyl, indanyl, indolyl and 1,2,4,4-tetrahydronaphthyl.
When a carbocyclic or heterocyclic group is substituted by two d-Cealkyl groups, the two alkyl groups can be combined together to form an alkylene chain, for example, a C3-alkylene chain. Carbocyclic or heterocyclic groups having this intertwined structure include bicyclo [2.2.2] octanyl and norbornyl.
The terms "kinase inhibitor" and "kinase activity inhibitor", and the like, are used to identify a compound that is capable of interacting with a kinase and inhibiting its enzymatic activity.
The term "inhibition of enzymatic kinase activity" is used to mean reducing the ability of a kinase to transfer a phosphate group from a donor molecule, such as ATP, to a specific target molecule (substrate). For example, the inhibition of kinase activity may be at least about 10%. In some embodiments of the invention, this reduction in kinase activity is at least about 25%, alternatively at least about 50%, alternatively at least about 75%, and alternatively at least about 90%. In other embodiments, the kinase activity is reduced by at least 95% and alternatively by at least 99%. The IC50 value is the concentration of kinase inhibitor that reduces the activity of a kinase to 50% of the uninhibited enzyme.
The terms "inhibitor of VEGF receptor signaling" are used to identify a compound having a structure as defined herein, which is capable of interacting with a VEGF receptor and inhibiting the activity of the VEGF receptor. In some embodiments, the activity reduction is at least about 50%, alternatively at least about 75%, and, alternatively at least about 90%. In some embodiments, the activity is reduced by at least 95% and alternatively by at least 99%.
The term "effective amount of inhibition" refers to designating a dose sufficient to cause inhibition of kinase activity. The amount of a compound of the invention that constitutes an "effective inhibiting amount" will vary depending on the compound, the kinase, and the like. The effective amount of inhibition can be determined routinely by those of ordinary skill in the art. The kinase can be in a cell, which in turn can be in a multicellular organism. The multicellular organism can be, for example, a plant, a fungus or an animal, for example, a mammal and, for example, a human being. The fungus may be infecting a plant or a mammal, for example, a human being, and therefore could be located in and / or in the plant or mammal.
In one embodiment example, such inhibition is specific, i.e., the kinase inhibitor reduces the ability of a kinase to transfer a phosphate group from a donor molecule, such as ATP, to a specific target molecule (substrate) at a lower concentration to the inhibitor concentration of what is required to produce another unrelated biological effect. For example, the concentration of the inhibitor required for the kinase inhibitory activity is at least two times lower, alternatively at least 5 times lower, alternatively at least 10 times lower, and, alternatively at least 20 times lower than the concentration required to produce an unrelated biological effect.
Thus, the invention provides a method for inhibiting the kinase enzyme activity, which includes contacting the kinase with an effective amount of inhibition of a compound or composition according to the invention. In some modalities, the kinase is found in an organism. Thus, the invention provides a method for inhibiting the enzymatic kinase activity in an organism, comprising administering to the organism an amount of effective inhibition of a compound or a composition according to the invention. In some embodiments, the organism is a mammal, for example a domesticated mammal. In some modalities, the organism is a human being.
The term "therapeutically effective amount" as used herein is an amount of a compound of the invention, which when administered to a patient, causes the desired therapeutic effect. The therapeutic effect depends on the disease to be treated and the desired results. As such, the therapeutic effect can be treatment of a disease state. In addition, the therapeutic effect may be inhibition of kinase activity. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the state of the disease and its severity, the age of the patient to be treated, among others. The therapeutically effective amount can be determined routinely by those of ordinary skill in the art.
In some embodiments, the therapeutic effect is the inhibition of angiogenesis. The phrase "inhibition of angiogenesis" is used to denote a capacity of a compound according to the present invention to retard the growth of blood vessels, such as blood vessels in contact with the inhibitor as compared to uncontacted blood vessels. In some modalities, angiogenesis is tumor angiogenesis. The phrase "tumor angiogenesis" is intended to designate the proliferation of blood vessels that come into contact or other contact with a cancerous tumor, such as a tumor. In some modalities, angiogenesis is the abnormal formation of the blood vessels of the eye.
In one embodiment example, angiogenesis is delayed by at least 25% compared to angiogenesis of the uncontacted blood vessels, alternatively at least 50%, alternatively at least 75%, alternatively at least 90%, alternatively at least the 95%, and, alternatively, at least 99%. On the other hand, angiogenesis is inhibited by 100% (ie, the blood vessels do not increase in size or number). In some embodiments, the phrase "inhibition of angiogenesis" includes regression in the number or size of blood vessels, as compared to uncontacted blood vessels. Thus, a compound according to the invention that inhibits angiogenesis can induce growth retardation of blood vessels, arrest of the growth of blood vessels, or induce the regression of the growth of blood vessels.
Thus, the invention provides a method for inhibiting angiogenesis in an animal, comprising administering to an animal in need of such treatment, a therapeutically effective amount of a compound or a composition of the invention. In some embodiments, the animal is a mammal, for example a domesticated mammal. In some modalities, the animal is a human being.
In some embodiments, the therapeutic effect is the treatment of a disease, disorder or ophthalmic condition. The phrase "treatment of an ophthalmic disease, disorder or condition" is to be understood as the ability of a compound according to the present invention for the treatment of a disease, disorder or exudative and / or inflammatory condition, ophthalmic related alteration of permeability and / or integrity of the retinal vessels, a disorder related to the rupture of retinal microvessels leads to a focal hemorrhage, a disease of the back of the eye, a disease of the retina, or a disease of the front of the eye, or another disease Ophthalmic disorder or condition In some embodiments, the disease, disorder or ophthalmic condition includes but is not limited to Age-Related Macular Degeneration (ARMD), exudative macular degeneration (also known as "wet" or age-related neovascular macular degeneration (wet ARMD), macular edema, age-related discoidal macular degeneration, cystoid macular edema, palpebral edema, retinal edema, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, chorioretinopathy , choroidal neovascularization, neovascular maculopathy, neovascular glaucoma, arterial and venous obstructive retinopathies (eg, retinal vein occlusion or retinal arterial occlusion), central retinal vein occlusion, disseminated intravascular coagulopathy, branched retinal venous occlusion, hypertensive background changes, of ocular ischemia, retinal arterial microaneurysms, coat disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papilloflebitis, central retinal artery obstruction, branched retinal artery occlusion, carotid artery disease (CAD), branching angiitis frozen, retinopath a of sickle cell and other hemoglobinopathies, angioid striae, macular edema that occurs as a result of etiologies, such as disease (eg, diabetic macular edema), ocular lesions or eye surgery, retinal ischemia or degeneration caused for example by injury, trauma or tumors, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epitheliitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, ulcer corneal, conjunctival ulcer, chronic nummular keratitis, Tigeson keratitis, progressive Mooren ulcers, an inflammatory ocular disease caused by a bacterial or viral infection or by an ophthalmic operation, an inflammatory ocular disease caused by physical injury to the eye, and a symptom for an inflammatory eye disease including p icor, rash, edema and ulcers, erythema multiforme exudative, erythema nodosum, erythema annulare, sclerodema, dermatitis, angioneurotic edema, laryngeal edema, glottic edema, subglottic laryngitis, bronchitis, rhinitis, pharyngitis, sinusitis, laryngitis or otitis media.
In some embodiments, the disease, disorder or ophthalmic condition includes but is not limited to age-related macular degeneration, diabetic retinopathy, retinal edema, retinal venous occlusion, neovascular glaucoma, retinopathy of prematurity, retinal pigmentary degeneration, uveitis, neovascularization corneal or proliferative vitreoretinopathy.
In some embodiments, the disease, disorder or ophthalmic condition is age-related macular degeneration, diabetic retinopathy or retinal edema.
Thus, the invention provides a method for treating the disease, disorder or ophthalmic condition in an animal, which includes administering to an animal in need of said treatment a therapeutically effective amount of a compound or composition of the invention. In some embodiments, the animal is a mammal, for example a domesticated mammal In some embodiments, the animal is a human.
In some modalities, the therapeutic effect is the inhibition of retinal neovascularization. The phrase "inhibition of retinal neovascularization" should be understood as the ability of a compound according to the present invention to retard the growth of the blood vessels of the eye, for example new blood vessels coming from the veins of the retina, for example, to retard the growth of new blood vessels from the veins of the retina and that extend along the inner (vitreous) surface of the retina.
In one embodiment example, retinal neovascularization is delayed by at least 25% compared to retinal neovascularization of uncontained blood vessels, alternatively at least 50%, alternatively at least 75%, alternatively at least 90%, alternatively at least 95% , and, alternatively, at least 99%. On the other hand, retinal neovascularization is inhibited by 100% (ie, blood vessels do not increase in size or number). In some embodiments, the phrase "inhibition of retinal neovascularization" includes regression in the number or size of blood vessels, as compared to uncontacted blood vessels. Thus, a compound according to the invention that inhibits retinal neovascularization can induce the retardation of the growth of blood vessels, arrest of the growth of blood vessels, or induce the regression of the growth of blood vessels.
Thus, the invention provides a method for inhibiting retinal neovascularization in an animal, comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or composition of the invention In some embodiments, the animal is a mammal, e.g., a domesticated mammal In some modalities, the animal is a human being.
In some embodiments, the therapeutic effect is the inhibition of cell proliferation. The phrase "inhibition of cell proliferation" is used to denote a capacity of a compound according to the present invention to retard the growth of cells in contact with the inhibitor compared to uncontacted cells. An evaluation of cell proliferation can be done by counting contacted and uncontacted cells using a Coulter cell counter (Coulter, Miami, Fl.) Or a hemocytometer. When the cells are in solid growth (eg, a solid or organ tumor), an evaluation of cell proliferation can be made by measuring growth with tweezers or comparing the size of the growth of the cells in contact with the cells not contacted In one embodiment example, the growth of the cells in contact with the inhibitor is delayed by at least 25% compared to the growth of the non-contacted cells, alternatively at least 50%, alternatively at least 75%, alternatively less 90%, alternatively at least 95%, and alternatively, at least 99%. By On the other hand, cell proliferation is 100% inhibited (ie, the contacted cells do not increase in number). In some embodiments, the phrase "inhibiting cell proliferation" includes a reduction in the number or size of cells contacted, as compared to uncontacted cells. Thus, a compound according to the invention that inhibits cell proliferation in a contacted cell can induce the cell in contact to undergo growth retardation, to undergo growth arrest, to undergo programmed cell death (i.e., apoptosis) , or experience necrotic cell death.
In some embodiments, the cell in contact is a neoplastic cell. The term "neoplastic cell" is used to denote a cell that shows aberrant cell growth. In some embodiments, the aberrant cell growth of a neoplastic cell increases cell growth. A neoplastic cell can be a hyperplastic cell, a cell that exhibits a lack of inhibition by in vitro growth contact, a benign tumor cell that is incapable of metastasis in vivo, or a cancer cell that is capable of in vivo metastasis and that can be repeated after the attempted elimination. The term "tumorigenesis" is used to denote the induction of cell proliferation that leads to the development of neoplastic growth.
In some modalities, the cell contacted is in an animal. Thus, the invention provides a method for treating a disease or cell proliferation condition in an animal, which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound or composition of the invention. In some embodiments, the animal is a mammal, for example a domesticated mammal. In some modalities, the animal is a human being.
The term "disease or condition of proliferating cells" is intended to refer to any condition that is characterized by aberrant cell growth, such as abnormally increased cell proliferation. Examples of such diseases or cell proliferative conditions treatable upon inhibition and treatment include, but are not limited to, cancer. Some examples of particular types of cancer include, but are not limited to, breast cancer, lung cancer, colon cancer, rectal cancer, bladder cancer, prostate cancer leukemia, and kidney cancer. In some embodiments, the invention provides a method for inhibiting the proliferation of neoplastic cells in an animal comprising administering to an animal having at least one neoplastic cell present in its body a therapeutically effective amount of a compound of the invention or a composition of the invention. same.
The term "patient" as used herein for purposes of the present invention includes humans and other animals, e.g., mammals, and other organisms. Thus, the compounds, compositions and methods of the present invention are applicable to both human therapy and veterinary applications. In some modalities the patient is a mammal, for example, a human being.
The terms "treat", "treatment", or the like, as used herein, cover the treatment of a disease state in an organism, and include at least one of: (i) prevention of the disease state from occurring; in particular, when such an animal is predisposed to the state of disease state but has not yet been diagnosed with it; (ii) the inhibition of the disease state, that is, partial or total arrest of its development; (iii) alleviating the disease state, i.e., causing the regression of the symptoms of the disease state, or alleviating a symptom of the disease, and (iv) reversing or regression of the disease state, such as elimination. or cured of the disease. In some embodiments of the present invention the organism is an animal, for example, a mammal, for example a primate, for example, a human. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction, severity of the disease, etc., may be necessary, and will be find out with routine experimentation by those with common knowledge in the technique. In some embodiments, the terms "treat", "treatment", or the like, as used herein, cover the treatment of a disease state in an organism and include at least one of (ii), (iii) and (iv) above .
Administration for diseases, disorders or non-ophthalmic conditions can be by any means, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal or intrarectal. In some embodiments, the compounds of the invention are administered intravenously in a hospital facility. In some modalities, the administration can be by oral route.
Examples of routes of administration of diseases, disorders and ophthalmic conditions include, but are not limited to, systemic, periocular, retrobulbar, intracanalicular, intravitral, topical injection (e.g., eye drops), subconjunctival injection, subtenon, transcleral, intracameral, subretinal, electroporation, and sustained release implant. Other routes of administration of other injection sites or other forms of administration for ophthalmic situations will be disclosed or contemplated by a person skilled in the art and are intended to be within the scope of the present invention.
In some embodiments of the present invention, routes of administration for diseases, diseases, and ophthalmic conditions include topical, subconjunctival, intravitreal, or other ocular routes, systemically, or other methods known to a person skilled in the art to a patient after administration. eye surgery.
In some other embodiments of the present invention, routes of administration of ophthalmic diseases, diseases and conditions include topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar or intracanalicular.
In some embodiments of the present invention, routes of Administration for diseases, diseases and ophthalmic conditions include topical administration (e.g., eye drops), systemic administration (e.g., oral or intravenous injection), subconjunctival injection, periocular injection, intravitreal injection, and surgical implant.
In some embodiments of the present invention, routes of administration for diseases, disorders and ophthalmic conditions include intravitreal injection, periocular injection, and sustained release implant.
In some embodiments of the present invention, an intraocular injection may be in the vitreous humor (intravitreal), below the conjunctiva (subconjunctival), behind the eye (retrobulbar), in the sclera, in the Tenon capsule (sub-Tenon) , or it may be in the form of a deposit.
The compounds of the present invention form salts that are also within the scope of the present invention. Reference to a compound of the invention, for example, a compound of formula (I), is hereinafter understood to include a reference to its salts, unless otherwise indicated.
The term "salt (s)", as used herein, denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, when a compound of the present invention comprises a base radical, such as, but not limited to a pyridine or imidazole and an acidic radical such as but not limited to a carboxylic acid, zwitterions ("inner salts") can be formed and are included within the term "salt (s)" as used herein. Pharmaceutically acceptable salts (ie, non-toxic (exhibiting minimal or no unwanted toxicological effects), physiologically acceptable) are preferred, although other salts are also useful, for example, in isolation or purification steps that can be employed during the preparation. The salts of the compounds of the invention can be formed, for example, by reaction of a compound of the present invention with an amount of acid or base, as an equivalent amount, in a medium such as one in which the salts precipitate or in an aqueous medium followed by lyophilization.
The compounds of the present invention which contain a basic radical, such as, but not limited to an amine or a pyridine or imidazole ring, can form salts with a variety of organic and inorganic acids. Examples of acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, eg, trifluoroacetic acid), adipates, alginates, ascorbates, aspartate, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, canforates , camphorsulfonates, cyclopentanopropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glycoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodietrates, hydroxyethane sulfonates (eg, 2-hydroxyethane sulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (for example, 2-naphthalenesulfonates), nichotinates, nitrates, oxalates, pectinates, persulphates, phenylpropionates (eg, 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulphates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, such toluenesulfonates such as tosylates, undecanoates, and the like.
The compounds of the present invention which contain an acidic radical, such as but not limited to a carboxylic acid, can form salts with a variety of organic and inorganic bases.
Examples of basic salts include the ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydramines (formed by N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Groups containing basic nitrogen can be quaternized with agents such as the lower alkyl halides (for example, methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl and diamyl sulfates) ), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and oth As used herein, the term "pharmaceutically acceptable salts" is intended to designate salts that retain the desired activity of the compounds identified above and show minimal or no unwanted toxicological effects. Examples of such salts include, but are not limited to, salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid. , oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and polygalacturonic acid. The other salts include pharmaceutically acceptable quaternary salts known to those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR + Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counter ion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate , and diphenylacetate).
Another aspect of the invention provides compositions comprising a compound according to the present invention. For example, in some embodiments of the invention, a composition comprises a compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug of a compound according to the present invention present in at least about 30% enantiomeric excess or diastereomeric In some embodiments of the invention, the compound, N-oxide, hydrates, solvate, pharmaceutically acceptable salt, complexes or prodrug is present in at least about 50%, in at least about 80%, or even at least about 90 % enantiomeric or diastereomeric excess. In some embodiments of the invention, the compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present in at least about 95%, alternatively at least about 98% and, alternatively at least about 99% excess of enantiomeric or diastereomeric In other embodiments of the invention, a compound, the N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is present as a substantially racemic mixture.
Some compounds of the invention may have chiral centand / or isomeric geometric cent(E- and Z-isom, and it is to be undood that the invention embraces all optical, enantiomeric, diastereoisomeric and geometric isom The invention also encompasses all tautomeric forms of the compounds described herein. When the compounds of the invention include chiral cent the invention encompasses the enantiomerically and / or diastereomerically pure isomof these compounds, the enantiomerically and / or diastereomerically enriched mixtures of said compounds, and the racemic and scala mixtures of said compounds. For example, a The composition may include a mixture of enantiomers or diastereomers of a compound of formula (I) in at least about 30% diastereomeric or enantiomeric excess. In some embodiments of the invention, the compound is present in at least about 50% enantiomeric or diastereomeric excess, in at least about 80% enantiomeric or diastereomeric excess, or even in at least about 90% enantiomeric excess or diastereomeric In some embodiments of the invention, the compound is present in at least about 95%, alternatively in at least about 98% enantiomeric or diastereomeric excess, and alternatively in at least about 99% enantiomeric or diastereomeric excess.
The chiral centers of the present invention can have the S or R configuration. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained either from chiral / intermediate precursors or from the racemates by any appropriate method, including without limitation, conventional methods, such as, for example, the formation of the salt with an optically active acid followed of crystallization.
The present invention also includes prodrugs of compounds of the invention. The term "prodrug" is intended to representing a compound covalently bound to a carrier, which prodrug is capable of releasing the active ingredient when the prodrug is administered to a mammal in question. The release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups, however, regenerate original functional groups by routine or in vivo manipulation. Prodrugs of the compounds of the invention include compounds wherein a hydroxy, amino, carboxylic or a similar group has been modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of the present invention) , amides (eg, trifluoroacetylamino, acetylamino, and the like), and the like.
The compounds of the invention can be administered, for example, as they are or as a prodrug, for example in the form of an in vivo hydrolysable ester or hydrolysable amide in vivo. An in vivo hydrolysable ester of a compound of the invention containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester that is hydrolysed in the human or animal body to produce the acid or alcohol of origin. Suitable pharmaceutically acceptable esters for carboxy include esters of d-Ceralkoxymethyl (eg, methoxymethyl), CrCealkanoyloxymethyl esters (eg, pivaloyloxymethyl), phthalidyl esters, C3-Cecycloalkoxycarbonyloxy-CrCealkyl esters (eg, 1-cyclohexylcarbonyloxyethyl); 1,3-dioxolen-2-onylmethyl esters (e.g., 5-methyl-1,3-d-oxolen-2-onylmethoxy) and CrC6alkoxycarbonyloxyethyl esters (e.g. methoxycarbonyloxyethyl) and can be formed in any appropriate carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a consequence of the in vivo hydrolysis of the decomposition of the ester gives the hydroxyl group originally. Examples of the α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester formation groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give esters of alkyl carbonate), dialkylcarbamoyl and N- (N, N-dialkylaminoethyl) -N-alkylcarbamoyl (to give carbamates), N, N-dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom through a methylene group to the 3- or 4- position of the benzoyl ring. A suitable value for a hydrolysable in vivo amide of a compound of the invention containing a carboxy group is, for example, an N-Cr Cealkyl or N, N-di-CrC6alkyl amide such as N-methyl, N-ethyl, N -propyl,?,? -dimethyl, N-ethyl-N-methyl, or?,? -diethyl amide.
Upon administration to a subject, the prodrug undergoes a chemical conversion by metabolic or chemical processes to give a compound of the present invention, for example, a salt and / or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.
Throughout the specification, modalities of one or more chemical substituents are identified. Also included are combinations of different modalities. For example, the invention describes some embodiments of D in the compounds and describes some modalities of group G. Thus, as an example, compounds in which examples of D are as described and where examples are contemplated within the scope of the invention as well. of group G are as described.
Compounds According to one embodiment, the invention provides compounds of formula (I): D- M (1) including N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and their complexes, and racemic and scala mixtures, diastereomers and enantiomers thereof, in which, D is selected from the group consisting of an aromatic, heteroaromatic, cycloalkyl or heterocyclic ring system, each of which is optionally substituted with 1 to 5 R38 independently selected; M is an optionally substituted heterocyclic fused radical; Z is -O-; Ar is a 5-7 membered aromatic ring system, which is optionally substituted with 0 to 4 R2 groups, and G is a group B-L-T, where B is -N (R 3) - or -C (= S) -; L is selected from the group consisting of -C (= 0) N (R13) -, -C (= O) C0-Cialkyl-C (= O) N (R13) -, and -C (= 0) -, wherein an alkyl group of the aforementioned group L is optionally substituted, and T is selected from the group consisting of -Co-C5alkyl, -C0. C5alkyl-Q, -O-C0-C5alkyl-Q, -O-C0-C5alkyl, -C (= S) -N (R13) -C0-C5alkyl-Q, -C0.C5alkyl-S (O) 2 -Q, and -C (= S) -N (R13) -C0-C5alkyl, wherein each C0. C5alkyl is optionally substituted; where each R38 is independently selected from the group consisting of halo, CrC6 optionally substituted alkyl, -Co-C6alkyl- (optionally substituted heterocycle), -C2-C6alkenyl = N-heterocycle-C6alkyl optionally substituted, -CH = N-optionally substituted heterocycle , - (CH2), NR39 (CH2) nR36, -C (0) (CH2) jNR39 (CH2) nR36, (CH2) jNR39 (CH2) [O (CH2)]] (CH2)) R99, - (CH2) jNR39C (0) (CH2) jO (CH2) jOR3, - (CH2) jNR39 (CH2) i (CH ) (NH2) (COOH), - (CH2) jNR39CH (CH3) (CH2) jR99 and - (CH2) jNR39 (CH2) jCOOH; where each j is a whole number independently varying from 0 to 4, alternatively 1 -2, n is an integer that varies from 0 to 6, x is an integer that goes from 0-6, alternatively 2-3, each i is independent 2 or 3, and the radicals - (CH2) n- of the above groups R38 are optionally substituted with C6alkyl; R36 is H or - (CH2) n3OR37; where n3 is an integer that varies from 0 to 6; with the proviso that when R36 and R39 are both bound to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen; each R37 is independently selected from H, C C6 alkyl, - (CH2) nO (CH2) aO-C C6alkyl, - (CH2) nCH (NH) (CH2) nO-C1-C6alkyl1 - (CH2) nCH (NH ) (CH2) nCrC6alkyl, - (CH2) nO (CH2) aO-C3-C10cycloalkyl, - (CH2) nCH (NH) (CH2) nO-C3-C10cycloalkyl and - (CH2) nCH (NH) (CH2) nC3- Cyclocycloalkyl, where each n is an integer independently ranging from 0 to 6 is already an integer ranging from 2 to 6, wherein the alkyl and cycloalkyl radicals of the above R37 groups are optionally substituted by one or more substituents selected from independently; R39 is selected from the group consisting of H, C C6 alkyl, -SO2-C C6alkyl, -C (0) -C C6 alkyl, -C (0) 0-C C6alkyl, -C (0) -C C6alkyl-NR3R3, -d-Cealkyl-O-CrCealkyl, -CiOXCH ^ cMOICbb ^ OC Cealkyl, -C (0) -Ci-C6alkyl-OH, -C (O) -CF3 and -C (0) CH [CH (CrC6alkyl) 2] NR3R3 and a protecting group used to protect secondary amino groups with the proviso that when R36 and R39 are both bound to the same nitrogen, then R36 and R39 are not both bound to nitrogen directly through an oxygen; R99 in each occurrence is independently -H, -NH2 or -OR3; R2 at each occurrence is independently selected from -H and halogen; each R3 is independently selected from the group consisting of -H and R4; R 4 is (C C 6) alkyl; each R13 is independently selected from the group consisting of -H, -C (0) NR3R3 and C C6 alkyl; Q is a ring system of three to ten members, optionally substituted with between zero and four of R20; Y each R20 is independently selected from the group formed by -H, halogen, trihalomethyl, -OR3, -S (O) 0-2R3, -S (0) 2NR3R3, -C (O) OR3, -C (0) NR3R3, - (CH2) 0-5 ( heteroanl), CrC6alkyl, - (CH2) nP (= 0) (Cr C6alkyl) 2, wherein n is an integer ranging from 0 to 6, and the heteroaryl and C C6 alkyl are optionally substituted.
In some embodiments of the compounds according to the present invention D is an aromatic or heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R38 groups.
In some embodiments according to the present invention, D is a 5- or 6-membered heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R38 groups.
In some embodiments according to the present invention, D is a 6-membered aromatic ring or 6-membered aromatic ring system, each of which is substituted with 1 or 2 independently selected R38 groups.
In some embodiments according to the present invention, D is a 6-membered aromatic ring system, substituted with 1 or 2 independently selected R38 groups.
In some embodiments according to the present invention, D is a 6-membered heteroaromatic ring system, substituted by 1 or 2 independently selected R38 groups.
In some embodiments according to the present invention, D is a 5-membered heteroaromatic ring system, substituted by 1 or 2 independently selected R38 groups.
In some embodiments of the present invention, D is selected from the group consisting of wherein the members of said group are substituted with 1 or 2 R38 groups selected independently.
In some embodiments of the present invention, D is selected from the group consisting of wherein the members of said group are substituted with 1 or 2 R38 groups selected independently.
In some embodiments according to the present invention, D is replaced by a group R38.
In some embodiments of the present invention, D is phenyl, pyridyl, or imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or 2 independently selected R38 groups.
In some embodiments according to the present invention, R38 is In some embodiments according to the present invention, D is phenyl, substituted by a group R38.
In some embodiments according to the present invention, D is pyridyl, substituted by 1 or 2 independently selected R38 groups.
In some embodiments according to the present invention, D is pyridyl, substituted with an R38.
In some embodiments according to the present invention, D is imidazolyl, substituted with one or two R38.
In some embodiments according to the present invention, D is imidazolyl, substituted by two R38.
In some embodiments of the present invention, D is tetrahydropyridyl substituted with 1 group R38.
In some embodiments of the present invention, each R38 is independently selected from the group consisting of C ^ Ce alkyl, - (CH2) jNR39 (CH2) j (CH) (NH2) (COOH), - (CH2) jNR39 (CH2) jCOOH, (CH2) jNR39 (CH2) i [0 (CH2) ¡] x (CH2) jR99, - (CH2) jNR39 (CH2) nR36 and -C0-C6alkyl- (optionally substituted heterocycle).
In some embodiments of the present invention each R38 is independently selected from the group consisting of C C6 alkyl, - (CH2) jNR39 (CH2) ¡[0 (CH2) i] x (CH2) jR99, and - (CH2) jNR39 ( CH2) nR36 In some embodiments of the present invention, each R38 is independently - (CH2) jNR39 (CH2) ¡[0 (CH2) ¡] (CH2) jR99 or (CH2) jNR39 (CH2) nR36.
In some embodiments of the present invention, R38 is - (CH2) jNR39 (CH2) nR36, where] is 1 and n is 2.
In some embodiments of the present invention R38 is - (CH2) NR39 (CH2) 2OCH3.
In some embodiments of the present invention, R38 is - (CH2)) NR39 (CH2) i [0 (CH2) i] x (CH2) jR99.
In some embodiments of the present invention, R38 is - (CH2) jNR39 (CH2) l [0 (CH2) i] x (CH2) jR99, where j is 1, i is 2, and x is 2 or 3.
In some embodiments of the present invention, D is pyridyl substituted with a - (CH2) jNR39 (CH2) nR36, alternatively a (CH2) jNR39 (CH2) nR36, where j is 1 and n is 2.
In some embodiments of the present invention, D is pyridyl substituted with a - (CH2) jNR39 (CH2) ¡[0 (CH2) ¡] x (CH2) jR99, alternatively a - (CH2) jNR39 (CH2) i [0 ( CH2) i] x (CH2) jOMe, where j is 1, i is 2, and x is 2 or 3.
In some embodiments of the present invention, D is pyridyl substituted with a (CH2) jNR39 (CH2) j (CH) (NH2) (COOH).
In some embodiments of the present invention, D is pyridyl substituted with a -C0-C6alkyl- (optionally substituted heterocycle), for example -C0-C6alkyl- (heterocycle substituted with an oxo).
In some embodiments of the present invention, D is pyridyl substituted with a - (CH 2) j NR 39 (CH 2) JCOOH.
In some embodiments of the present invention, D is pyridyl substituted with a - (CH2) jNR39C (0) (CH2) 0 (CH2) ¡OR3.
In some embodiments of the present invention D is tetrahydropyridyl substituted with an optionally substituted -CH = N-heterocycle.
In some embodiments of the present invention D is tetrahydropyridyl substituted with a -C (0) (CH2) jNR39 (CH2) nR36.
In some embodiments of the present invention, D is imidazolyl substituted with a C6alkyl C and a - (CH2) jNR39 (CH2) rR36.
In some embodiments of the present invention, D is phenyl substituted with a - (CH2) jNR39 (CH2) ¡[0 (CH2) ¡] x (CH2) jR99 In some embodiments of the present invention, R39 is selected from the group consisting of H, -C (0) -CrC6 alkyl (e.g., -C (O) -Me), -C (0) -0-CrC6 alkyl, -C (0) -C -C6alkyl-NH2, -S02-Me, -C (0) (CH2) o-40 (CH2) i.40CrC6alkyl and -C (O) CH [CH (Ci-C6alkyl) 2] NR3R3 .
In another embodiment of the present invention, R39 is selected from the group consisting of H, -C (0) -e, C (O) (CH2) O (CH2) 20C1alkyl and -C (0) CH (CHMe2) NH2.
In some embodiments of the present invention, R39 is H or -C (0) -Me.
In some embodiments of the present invention, R39 is H. In some embodiments of the present invention R36 is -OMe.
In some embodiments of the present invention, R99 is -OMe.
In some embodiments of the present invention, M is * represents the point of attachment to D, and † represents the point of attachment to Z.
In some embodiments of the present invention, Ar is selected from the group consisting of phenyl, pyrazine, pyridazine, pyrimidine and pyridine, wherein each of said phenyl, pyrazine, pyridazine, pyrimidine and pyridine is optionally substituted by 0 to 4 groups R2.
In some embodiments of the present invention, Ar is phenyl, optionally substituted by 0 to 4 groups R2, alternatively with 1 or 2 groups R2, alternatively with 0, 1 or 2 halo.
In some embodiments of the present invention, Ar is phenyl substituted with a halo, for example, an F.
In some embodiments of the present invention, G is selected from the group consisting of In some embodiments of the present invention, G is selected from the group consisting of In some embodiments of the present invention, G is selected from the group consisting of In some embodiments of the present invention, Q is selected from the group consisting of phenyl, cyclopropyl, isoxazolyl, cyclohexyl, thiazolyl, tetrahydrofuran, pyrazolyl, cyclobutyl and cyclopentyl, optionally substituted with between zero and two R20.
In some embodiments of the present invention, Q is phenyl, optionally substituted with one or two R20.
In some embodiments of the present invention, Q is cyclopropyl.
In some embodiments of the present invention Q is tetrahydrofuran.
In some embodiments of the present invention, Q is pyrazolyl optionally substituted with an R20.
In some embodiments of the present invention, each R20 is independently selected from the group consisting of -P (= 0) (Me) 2, methyl, halo (eg, F), trihalomethyl, methoxy, -C (0) NH2, heteroaryl, COOH, -S02NH2, -C (0) NH2, COOMe-, -C (0) N (H) (Me), -C (0) N (Me) 2 and -SO2Me.
In some embodiments of the present invention, Q is substituted with an R20 selected from -P (= 0) (Me) 2, methyl and methoxy.
In some embodiments of the present invention, Q is phenyl substituted with a -P (= 0) (Me) 2.
In some embodiments of the present invention, Q is pyrazolyl, isoxazolyl or thiazolyl substituted with a methyl.
In some embodiments of the present invention, D is phenyl, pyridyl, imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or 2 independently selected R38 groups; Month Z is -O-; Ar is phenyl optionally substituted by 0 to 4 R2 groups, for example with between zero and four halo; Y G is selected from the group consisting of 20 wherein Q is optionally substituted with from 0 to 4 R selected independently.
In some embodiments of the present invention, D is pyridyl substituted with (CH2) jNR39 (CH2) i [0 (CH2)]] x (CH2) jR99, -C0-C6alkyl- (heterocycle optionally substituted with one or two oxo), - (CH2) jNR39 (CH2) jCOOH, CH2) j (CH) (NH2) (COOH); Month Z is -O-, Ar is phenyl optionally substituted by 0 to 4 groups R2, for example, an F, and G is wherein Q is optionally substituted with 0 to 4 R-independently selected.
In some embodiments of the present invention, D is pyridyl substituted with - (CH2) iNR39 (CH2) nR36, - (CH2) jNR39 (CH2) ¡[O (CH2) ¡] x (CH2) jR99, -C0-C6alkyl- (heterocycle substituted with oxo), - (CH2) jNR39 (CH2) jCOOH or - (CH2) jNR39 (CH2) j (CH) (NH2) (COOH); R "is OMe Month Z is -0-; Ar is phenyl optionally substituted by 0 to 4 R2 groups, eg, phenyl substituted with an F, and G is where R13 is H; Y Q is phenyl optionally substituted with 1 or 2 R20 selected independently, wherein each R20 is independently selected from the group consisting of -P (= 0) (Me) 2, methyl, halo (eg, F), trihalomethyl, methoxy, -C (0) NH2, heteroaryl, -COOH, -S02HN2, -C (0) NH2, -COOMe, -C (0) N (H) (Me), -C (O) N (Me) 2 and -S02Me or Q is pyrazolyl optionally substituted with methyl, or Q is cyclopropyl, cyclobutyl or tetrahydrofuran, or Q is isoxazolyl substituted with methyl.
In some embodiments of the present invention, D is pyridyl substituted with - (????? - ??? ^) ^ > 36 (CH2) jNR39 (CH2) i [0 (CH2) ¡] x (CH2) jR99, -C0-C6alkyl- (heterocycle substituted an oxo), (CH ^ NR ^ CH ^ COOH or - (CH2) jNR39 (CH2) J (CH) (NH2) (COOH); R "is OMe; Month Z is -0-; Ar is phenyl optionally substituted with 0 to 4 R2 groups, for example, phenyl substituted with an F, and G is where R13 is H; Y Q is cyclopropyl.
In some embodiments of the present invention, D is pyridyl substituted with -C0-C6alkyl- (optionally substituted heterocycle); Month Z is -O-; Ar is phenyl optionally substituted with 0 to 4 R2 groups, for example, phenyl substituted with an F, and G is R13 R13 o o where R1 J is H; Y Q is cyclopropyl.
In some embodiments of the present invention, D is pyridyl substituted with -C0-C6alkyl- (heterocycle optionally substituted with one or two oxo), for example -CH2- (5- or 6-membered heterocyclyl substituted with 0, 1 or 2 oxo); Month Z is -O-; Ar is phenyl optionally substituted with 0 to 4 groups R2, for example, phenyl substituted with an F, and G is R13 R13 O o where R1JesH, and Q is cyclopropyl.
In some embodiments of the present invention, D is pyridyl substituted with Month Z is -O-; Ar is phenyl optionally substituted with 0 to 4 R groups, for example, phenyl substituted with an F, and G is R13 R13 0 or where R13 is H; Y Q is cyclopropyl.
In some embodiments of the present invention, D is pyridyl substituted with - (CH 2) j NR 39 (CH 2) i [0 (CH 2) i]) < (CH2) jR R "is OMe; Month Z is -O-; Ar is phenyl optionally substituted with 0 to 4 groups R2, for example, phenyl substituted with an F, and G is where R13 is H; Y Q is cyclopropyl.
In some embodiments of the present invention, D is imidazolyl substituted with a C6alkyl and a (CH2) jNR39 (CH2) jR36; Month Z is -O-; Ar is phenyl optionally substituted with 0 to 4 groups R2, example an F, and G is Where Q is optionally substituted with from 0 to 4 independently selected R20.
In some embodiments of the present invention, D is imidazolyl substituted with a CrC6alkyl and a - (CH2) jNR39 (CH2) nR36; Month Z is -O-; Ar is phenyl optionally substituted with 0 to 4 R groups, for example, phenyl substituted an F, and G is R13 R13 0 or 0) where R13 is H, and twenty Q is phenyl optionally substituted with 0 to 4 R selected independently, In some embodiments of the present invention, D is midazolyl substituted with a C6alkyl and a - (CH2) jNR39 (CH2) nR36; Month Z is -O-; Ar is phenyl optionally substituted with 0 to 4 R2 groups, for example, phenyl substituted with an F and G is R 13 R 13 0 or 0; where R13 is H, and Q is phenyl optionally substituted with one or two groups independently selected from the group consisting of -P (O) Me.sub.2, methyl, halo (for example, F), trihalomethyl (for example trifluoromethyl), methoxy, -C (O) NH.sub.2 and heteroaryl (for example, oxazoliium), or Q is cyclopropyl.
The compounds of the above formulas can generally be prepared according to the following schemes. Tautomers and solvates (eg, hydrates) of the compounds of the above formulas are also in the scope of the present invention. Solvation methods are generally known in the art. Accordingly, the compounds of the present invention may be in free form, hydrate or salt form, and may be obtained by methods exemplified by the following schemes below.
The following examples and preparations describe the manner and process for making and using the invention and are illustrative rather than limiting. It should be understood that there may be other embodiments that fall within the spirit and scope of the invention as defined in the appended claims.
Compounds according to the invention include, but are not limited to those described in the following examples. Compounds are named with Chemdraw Ultra version 10.0 or version 8.0.3, which are available through Cambridgesoft.com, 100 Park Drive Cambridge, Cambridge, MA 02140, or are derived from it.
The data presented here demonstrate the inhibitory effects of the kinase inhibitors of the invention. These data lead us to reasonably expect that the compounds of the invention be useful not only for the inhibition of kinase activity, the protein tyrosine kinase activity, or modalities thereof, such as VEGF receptor signaling, but also as therapeutic agents for the treatment of proliferating diseases, such as cancer and the growth of tumors and diseases, diseases and ophthalmological conditions.
Synthesis schemes and experimental procedures The compounds of the invention can be prepared according to the reaction schemes or the examples illustrated below using methods known to those of ordinary skill in the art. These schemes serve to exemplify some procedures that can be used to make the compounds of the invention. One skilled in the art will recognize that other general synthetic methods can be used. The compounds of the invention can be prepared from starting components that are commercially available. Any type of substitutions can be made to the starting components to obtain the compounds of the invention according to procedures that are well known to those skilled in the art.
SPECIFIC EXAMPLES SCHEME 1 46 (2- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b1pyridin-2-yl) -1-methyl-1 H-imidazol-5-yl) methyl (2-methoxyethyl) carbamate tere -butyl (46) Stage 1 . 5- (1, 3-dioxan-2-yl) -1-methyl-1 H-imidazole (38) fShafiee A., N. Rastkary, M. Jorjani, M., Shafaqhi B., Arch. Pharm. Pharm Med Chem. 2002, 2, 69 -761 To a solution of 1-methyl-1 H-imidazole-5-carbaldehyde (2.9 g, 26.3 mmol) in toluene (20 mL) is added propane-1,3-diol (4.01 g, 52.7 mmol) and CSA (0.306 g). , 1317 mmol) and the reaction mixture is heated to reflux with the azeotropic removal of the developed water for 24 hours. The reaction mixture is cooled to RT, diluted with DCM and washed with NaHCO3 solution. It was then dried over Na 2 SO 4, filtered and concentrated. Purification by column chromatography (80% EtOAc in hexane to EtOAc) yields 38 (2.53 g, 57% yield) as a yellow oil which solidifies on standing to a yellow solid.
MS (m / z): 169.2 (M + H).
Step 2. 5- (1, 3-D-oxane-2-yl) -2-iodo-1-methyl-1 H -amidazole (39) To a solution of 38 (295 g, 1754 mmol) in dry TF (10 ml) at -78 ° C n-BuLi (0.772 ml, 1.929 mmol, 2.5 M in hexanes solution) is added and the reaction mixture is stirred for 20 minutes. Iodine (445 mg, 1754 mmol) in THF (2 mL) is added dropwise slowly while maintaining the temperature at -78 ° C and the reaction mixture is stirred for another 30 minutes. minutes, and quenched by the addition of water and then extracted with EtOAc. The organic phase is washed with sodium thiosulfate solution, separated, dried over Na 2 SO 4, filtered and concentrated. Purification by column chromatography (20% EtOAc / hexane) yields 39 (305 mg, 59% yield) as a white solid.
MS (m / z): 294.1 (M + H).
Step 3. 2- (5- (1,3-dioxan-2-yl) -1-methyl-1 H-imidazol-2-yl) -7-chlorothienof3,2-blpyridine (40) To a solution of 7-chlorothieno [3,2-b] pyridine (1) [Klemm, L.H .; Louris, J.N; Boisvert, W. Higgins, C; Muchiri, D.R .; J. Heterocyclic Chem., 22, 1985, 1249-1252] (11.7 g, 69.0 mmol) in THF (300 mL) is added, at -78 ° C, a solution of n-BuLi (30.46 mL, 76 mmol , 2.5 M in hexanes) and the reaction mixture is stirred for 10 minutes. A solution of ZnCl2 (76.15 mL, 76 mmol, 1.0 M in Et20) is added and the mixture is stirred at room temperature for 10 minutes. Pd (PPh3) 4 (2287 mg, 0.104 mmol) is added together with a solution of 39 (5.82 g, 19.79 mmol) in THF (20 mL) and the reaction mixture is refluxed under N2 gas atmosphere for 4 hours . The reaction is then cooled to RT, and diluted with ammonium hydroxide and EtOAc. The organic phase is collected, dried over Na 2 SO 4, filtered and concentrated. The resulting material is triturated with Et20 to yield the title compound 40 (5.79 g, 87% yield) as a white solid.
MS (m / z): 336.1 (M + H).
Step 4. 2- (5- (1,3-dioxan-2-yl) -1-methyl-1 H-imidazol-2-yl) -7- (2-fluoro-4-nitrophenoxy) thieno [3,2 -blpyridine, (41) A mixture of 40 (5.9 g, 17.57 mmol), 2-fluoro-4-nitrophenol (5.52 g, 35.1 mmol) and NaHCO 3 (1346 g, 16.02 mmol) in Ph20 (7 mL) is heated at 180 ° C for 4 hours. The reaction mixture is cooled to RT and diluted with DCM, filtered and concentrated. Purification of the residue by column chromatography (eluent EtOAc) gives 41 (2.5 g, 31% yield) as a yellow solid.
MS (m / z): 457.1 (M + H).
Step 5. 2- (5- (D-Methoxymethyl) -1-methyl-1 H-imidazol-2-yl) -7- (2-fluoro-4-nitrophenoxy) thienof3,2-b1-pyridine (42) To a solution of 41 (2.5 g, 5.48 mmol) in MeOH (200 mL) is added CSA (127 mg, 0.548 mmol) and the reaction mixture is refluxed for 5 hours. It is then cooled to RT and solid NaHCO 3 is added. The mixture is filtered and the filtrate is concentrated to dryness. The solid residue is dissolved in DCM, washed with water, dried over Na2SO, filtered and concentrated. The resulting solid is triturated with Et2O to yield 42 (1.8 g, 74% yield) which is used without further purification.
MS (m / z): 445.1 (M + H).
Step 6. 2- (7- (2-fluoro-4-nitrophenoxy) thienor3,2-blpyridin-2-yl) -1-methyl-1 H-imidazole-5-carbaldehyde (43) To a solution of 42 (1.8 g, 4.05 mmol) in acetone (100 mL) and water (100 mL) is added diluted HCl (20 mL, 2 M, 40.0 mmol) and the reaction mixture is stirred at room temperature night. It is then concentrated until dry. The solid residue is dissolved in DCM, washed with water, dried over Na 2 SO 4, filtered and concentrated. The resulting solid is triturated with Et20 to yield 43 (1.3 g, 81% yield), which is used without further purification.
MS (m / z): 399.2 (M + H).
Step 7. N - ((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-blpyridin-2-yl) -1-methyl-1 H-imidazol-5-yl) methyl) - 2-methoxyethamine (44) To a suspension of 43 (1.3 g, 3.26 mmol) in dry DCM (50 ml) at room temperature is added 2-methoxyethamine (1226 g, 16.32 mmol), acetic acid (0.98 g, 16.32 mmol) and sodium triacetoxyborohydride (3.46). g, 16.32 mmol), and the reaction mixture is stirred at room temperature for 24 hours. It is then diluted with additional DCM and washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to dryness to give 44 (1.5 g, 100% yield) as a yellow oil which is used as a crude oil. the next stage without further purification.
MS (m / z): 458.2 (M + H).
Step 8. (2- (7- (2-fluoro-4-nitrophenoxy) thienof3,2-blpyridin-2-yl) -1-methyl-1 H-imidazol-5-yl) methyl (2-methoxyethyl) tere-butyl carbamate (45) To a solution of 44 (1.5 g, 3.28 mmol) in DCM (50 mL) at room temperature is added Boc20 (1073 mg, 4.92 mmol) and the reaction mixture is stirred at room temperature overnight. The mixture is concentrated to dryness and the residue is purified by column chromatography (eluent EtOAc) to yield 45 (1.3 g, 71% yield) as a yellow solid.
MS (m / z): 558.2 (M + H).
Step 9. (2- (7- (4-amino-2-fluorophenoxy) thienor3,2-blpyridin-2-yl) -1-methyl-1 H-imidazol-5-yl) methyl (2-methoxyethyl) carbamate of tere -butyl (46) To a solution of 45 (1.1 g, 0.717 mmol) in eOH (30 mL) and water (10 mL) is added ammonium chloride (211 mg, 3.95 mmol) and zinc (1.61 g, 17.76 mmol) and the mixture of reaction is heated at reflux for 24 hours. The reaction mixture is cooled to RT then concentrated to dryness. The residue is partitioned between DCM and water and the organic phase is collected, dried over Na 2 SO 4, filtered and concentrated to yield the title compound 46 (1.04 g, 100% yield), which is used crude in the next stage without further purification.
MS (m / z): 528.1 (M + H).
SCHEME 9 126 (6- (7- (4-amino-2-fluorophenoxy) thienof3,2-b1pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate tere-butyl (126) Step 1. N - ((6-Bromopyridin-3-yl) methyl) -2-methoxyethamine (143) To a solution of 6-bromopyridine-3-carbaldehyde (5 g, 26.9 mmol) in DCM (40 ml), add 2-methoxyethylamine (2.80 ml, 32.3 mmol). After 10 minutes, sodium triacetoxyborohydride (7.98 g, 37.6 mmol) is added to the mixture and stirred at RT for 17 hours. DCM (100 mL of water (50 mL and NH4CI (50 mL) is added to the reaction mixture.The organic phase is collected and the aqueous layer is extracted with DCM (3 x 100 mL) .The combined organic solutions are washed with Brine and concentrate under reduced pressure The residue is purified by flash column chromatography, eluent 98/2 to 95/5 DCM / MeOH, to give titer 143 (2958 g, 45% yield) as a brown oil. 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 8.31 (dd, J = 2.6, 0.6 Hz, 1 H), 7.70 (dd, J = 8.2, 2.6 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 3.69 (s, 2H), 3.37 (t, J = 5.8 Hz, 2H), 3.22 (s, 3H), 2.60 (t, J = 5.8 Hz, 2H).
MS (m / z): 245.1 (M + H).
Stage 2. Tere-Butyl (6-Bromopyridin-3-yl) methyl (2-methoxyethyl) carbamate (144) To a solution of 143 (13,072 g, 53.3 mmol) in TF (40 mL) is added di-tert-butyl dicarbonate (14.86 mL, 64.0 mmol). The mixture is stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue is purified by flash column chromatography, eluent hexane / EtOAc: 7/3, 6/4, 5/5, to give the title compound 144 (16.196 g, 88% yield) as a yellow oil.
H NMR (400 MHz, DMSO-d6) d (ppm): 8.26 (dd, J = 2.4, 0.8 Hz, 1 H), 7.64-7.58 (m, 2H), 4.39 (s, 2H), 3.40-3.33 ( m, 4H), 3.20 (s, 3H), 1 .41 -1.31 (m, 9H).
MS (m / z): 345.2 (M + H).
Step 3. (6- (7-chlorothieno [3,2-blpyridin-2-yl) pyridin-3-yl) methyl (tere-butylcarbamate-2-methoxyethylcarbamate (145) To a solution of 7-chlorothieno [3,2-b] pyridine (1) (8.84 g, 52.1 mmol) in TF (100 mL) at -78 ° C is added n-butyllithium (20.86 mL, 52.1 mmol) . After 30 minutes, zinc chloride (52.1 ml, 52.1 mmol) (1 M in ether) is added at -78X and the reaction mixture is warmed to room temperature. After 1 hour, tetrakistriphenylphosphine palladium (1,004 g, 0.869 mmol) and 144 (6 g, 17.38 mmol) in THF (25 ml) are added and the mixture is heated at reflux for 1 hour. This is then partitioned between saturated aqueous solution NaHCO 3 and EtOAc. The organic layer is collected and the aqueous layer is extracted with EtOAc (3x100 ml). The combined organic layers are washed with brine and evaporated under reduced pressure. The residue is purified by flash column chromatography, hexane / EtOAc: 5/5, 3/7, 0/10, to give compound 145 (5.41 g, 72% yield). 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 8.65 (d, J = 5.1 Hz, 1 H), 8.52 (d, J = 1.6 Hz, 1 H), 8.39 (s, 1 H), 8.27 (d, J = 8.0 Hz, 1 H), 7.80 (dd, J = 8.1, 2.1 Hz, 1 H), 7.58 (d, J = 5.1 Hz, 1 H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33 (m, 9H).
MS (m / z): 434.2 (M + H).
Step 4. (6- (7- (4-Amino-2-fluorophenoxy) thienof3,2-blpyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate tere-butyl (126) To a solution of 4-amino-2-fluorophenol (1.933 g, 15.21 mmol) in DMSO (30 mL) is added potassium tert-butoxide (2.017 g, 17.97 mmol). After 30 minutes, chloride 145 (6 g, 13.83 mmol) is added and the reaction mixture is heated at 100 ° C for 45 minutes. The mixture is cooled and then poured into water (250 ml) at 40-45X and stirred for 30 minutes. The precipitate is collected by filtration, washed with water (2 x 30 ml) and dried overnight. The crude solid is triturated with Et2O (50 ml) for 1 hour to give the title compound 126 (4.18 g, 58% yield) as a brown solid.
MS (m / z): 525.2 (M + H).
SCHEME 14 + g.Me Pd2 (dba) 3. xanlfos M _ "N ° 2 H Me Cs2C03, Dioxane 90 ° C, 3 hours 287 289: example 179 EXAMPLE 179 1 - . 1 - (3- (Dimethylphosphoryl) phenyl) -3- (3-fluoro ^ - (2- (5 - ((2-methoxyethylamino) methyl) -pyridin-2-yl) thienor 3,2-b1pyridin-7 ilox!) phenyl) urea (289) Step 1. 1 - (dimethylphosphoryl) -3-nitrobenzene (286) Dimethylphosphine oxide is added to a solution of 1-iodo-3-nitrobenzene (2.4 g, 9.6 mmol) in dry 1,4-dioxane (24 mL) in a pressure vessel with nitrogen at room temperature [WO 2005/009348] (1.5 g, 19.2 mmol), Pd2 (dba) 3 (0.44 g, 0.48 mmol), Xantphos (0.56 g, 0.96 mmol) and cesium carbonate (4.38 g, 13.5 mmol). The mixture is degassed by bubbling nitrogen into the solution for 10 minutes. The pressure bottle is closed and heated to 90 ° C for 3 hours. The solvent is removed under reduced pressure and the residue is purified with Biotage (linear gradient 0-20%, methanol / ethyl acetate, 25 M column) to yield the title compound 286 as a brown solid (1.52 g, 7.63 mmol, 79%).
MS (m / z): 200.1 (M + H).
Step 2. 3- (dimethylphosphoryl) aniline (287) To a solution of compound 286 (1.5 g, 7.5 mmol) in methanol (62 ml) and water (12 ml) under nitrogen at room temperature are added ammonium chloride (0.604 g, 11.3 mmol) and iron (1.68 g, 30.1 mmol). The resulting mixture is refluxed for 30 minutes then filtered through celite. The celite pad is rinsed with methanol. The filtrate and washings are combined and concentrated and the residue is purified with Biotage (linear gradient 0-20%, methanol / dichloromethane, 25 M column) to yield compound 287 as a yellow solid (1.27 g, 7.51 mmol, quantitative).
MS (m / z): 170.1 (M + H).
Step 3. (6- (7- (4- (3- (3- (dimethylphosphoryl) phenyl) ureido) -2-fluorophenoxy) thienof3,2-blpyridin-2-yl) pyridn-3-yl) methyl (2- tert-butyl methoxyethyl) carbamate (288) To a solution of compound 126 (schemes 6 or 9) (200 mg, 0.381 mmol) in dry tetrahydrofuran (8 ml) under nitrogen at -20 ° C is added 4-nitrophenyl chloroformate (115 mg, 0.572 mmol). The reaction mixture is stirred at -20 ° C for 2 hours. A solution of 3- (dimethylphosphoryl) aniline 287 (97 mg, 0.57 mmol) and?,? '-diisopropylethylamine (0.200 mL, 1.14 mmol) in a mixture of dry tetrahydrofuran (2 mL) and dry?,?' - dimethylformamide ( 2 ml) are added at -20 ° C, the reaction mixture is allowed to warm to room temperature slowly, and the stirring is maintained for an additional 16 hours. The solvent is removed under reduced pressure, the residue is diluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated. Purification through Biotage (linear gradient 0-20%, methanol / dichloromethane, column 25M) yields compound 288 (230 mg, 0.32 mmol, 84%).
MS (m / z): 720.4 (M + H).
Step 4. 1- (3- (dimethylphosphoryl) phenyl) -3- (3-fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2 -blpyridin-7-yloxy) phenyl) urea (289) To a solution of compound 288 (30 mg, 32 mmol) in dichloromethane (7 ml) under a nitrogen atmosphere at room temperature is added trifluoroacetic acid (2.5 ml, 32 mmol). The reaction mixture is Stir for 16 hours at room temperature. The solvent is removed under reduced pressure and a saturated aqueous solution of sodium bicarbonate is added. The aqueous phase is extracted with ethyl acetate (3X), the combined organic layers are concentrated. The residue is purified with Biotage (linear gradient 0-20%, methanol / dichloromethane, 25 M column) to give 289 as a whitish compound (75.3 mg, 0.122 mmol, 38.0%). 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 9.15 (s, 1 H), 9.06 (s, 1 H), 8.57 (d, J = 1.6 Hz, 1 H), 8.53 (d, J = 5.6 Hz, 1 H), 8.31 (s, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 7.92-7.83 (m, 2H), 7.76 (dd, J = 13.2, 2.4 Hz, 1 H ), 7.67-7.62 (m, 1 H), 7.49-7.42 (m, 2H), 7.41 -7.33 (m, 1 H), 7.32-7.26 (m, 1 H), 6.67 (d, J = 5.6 Hz, 1 H), 3.78 (s, 2H), 3.54-3.34 (2H, hidden under the water signal), 3.24 (s, 3H), 2.65 (t, J = 5.6 Hz, 2H), 1.65 (d, J = 13.2 Hz, 6H) MS (m / z): 620.4 (M + H).
EXAMPLE 180 1- (4- (Dimethyl-phospho-phenyl) -3- (3-fluoro ^ - (2- (5 - ((2-methoxyethylamino) methy1) pyridin-2-yl) thienof3,2-b1-pyridin-7-yloxy) phenyl )urea (290) Compound 290 is obtained by following the procedures described above for compound 289 (Example 179). Characterization of compound 290 and compounds 295-300 are presented in table 1 TABLE 1 SCHEME 16 315: example 202 EXAMPLE 202 Step 1. (2- (7- (2-fluoro-4- (3-isopropylureido) phenoxy) thienof3,2-b1-pyridin-2-yl) -1-methyl-H-imidazol-5-yl) methyl (2- tert-butyl methoxyethyl) carbamate (314) The reaction mixture of aniline 46 (200 mg, 0.379 mmol) and 2-isocyanatopropane (64.5 mg, 0.758 mmol) is heated at 100X for 15 minutes in a microwave reactor. The reaction mixture is loaded directly into Biotage (Silicycle, HR, column 12g, 50-100% EA / hexane, then MeOH / EA, 0-20%). The collected fractions yield the desired product 314 (150 mg, 0.245 mmol, 64.6% yield) as a white solid. MS: 613 (MH) +, very weak signal.
Step 2. 1 - (3-Fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) -1-methyl-H-imidazol-2-yl) thienof3,2-b1pyridin-7-yloxy ) pheny1) -3-isopropylurea (315) The solution of urea 314 (150 mg, 0.245 mmol) and TFA (1 mL, 12.98 mmol) in DCM (20 mL) is stirred 4 hours at room temperature and concentrated. The residue is partitioned between EtOAc / saturated solution aHC03. The solid is collected by filtration and combined with organic layer. The mixture is concentrated and the residue is purified through Biotage (EA / MeOH 0-40%, column 12g Silicycle HR). Collected fractions give the desired product 315 (70 mg, 0.137 mmol, 55.8% yield) as a white solid. 1 H NMR (dmso-d 6) 5 (ppm) 1 H: 8.67 (s, 1 H), 8.48 (d, 1 H, J = 5.5Hz), 7.91 (s, 1 H), 7.65 (dd, 1 H, J1 = 13.7Hz, J2 = 2.6Hz), 7.32 (t, 1 H, J = 9.0Hz), 7.07 (m, 2H ), 6.63 (d, 1 H, J = 5.5Hz), 6.13 (d, 1 H, J = 7.6Hz), 4.04 (s, br, 2H), 3.08 (s, 3H), 3.72 (m, 1 H) ), 3.47 (t, 2H, J = 5.2Hz), 3.24 (s, 3H), 2.94 (m, 2H), 1.07 (s, 3H, 1.05 (s, 3H) (presumably urn salt mono-TFA). : 513.4 (MH) +.
SCHEME 17 Step 4. 4- (2- (5- (1,3-dioxane-2-yl) thienof3,2-blpyridin-7-yloxy) -3-fluoroaniline (319) Step 1. 2-Bromo-5- (1,3-dioxan-2-yl) pyridine (316) To a solution of 6-bromopyridine-3-carbaldehyde (25 g, 134 mmol) in toluene (130 mL) is added 1,3-propanediol (20.45 g, 269 mmol) and 10-camphorsulfonic acid (3.12 g, 13.44 mmol). . The reaction mixture is heated to reflux, with azeotropic removal of the developed water, for 50 minutes, cooled to room temperature and concentrated. The residue is partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 solution (100 mL). The organic phase is collected and the aqueous phase is extracted with EtOAc (2 x 150 mL). The combined organic fractions are washed with brine (100 ml), dried over Na 2 SO 4, filtered and concentrated to give a brown solid which is triturated with Et 2 O and hexane (10/200 ml) to give intermediate 316 (27.7 g). , 84% yield) as a beige solid.
MS (m / z): 244.1, 246.1 (M + H). 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 8.40 (d, J = 2.4 Hz, 1 H), 7.35 (dd, J = 8.0, 2.4 Hz, 1 H), 7.66 (dd, J = 8.0 , 0.4 Hz, 1 H), 5.61 (s, 1 H), 4.15 (ddd, J = 11.8, 5.0, 1.2 Hz, 2H), 3.98-3.91 (m, 2H), 2.028-1.95 (m, 1 H) , 1 .46 (d quintuplet, J = 13.2, 1.2 Hz, 1 H).
Step 2. 2- (5- (1,3-dioxane-2-yl) pyridin-2-yl) -7-chlorothienof3.2-blpyridine (317) To a solution of 7-chlorothieno [3,2-b] pyridine (1) (13.33 g, 79 mmol) in THF (204 ml) at -5 ° C / -10 ° C is added n-BuLi (2.5 M in hexanes, 31.6 mL, 79 mmol) for 50 minutes. After 30 minutes, a solution of zinc chloride in ether (1 M, 79 mL, 79 mmol) is added at -5 ° C / -10 ° C for 50 minutes and the reaction mixture is allowed to warm to room temperature. After 45 minutes, 2-bromo-5- (1, 3-dioxan-2-yl) pyridine (316) (15.98 g, 65.5 mmol) and tetrakistriphenylphosphine palladium (2.27 g, 1.964 mmol) in THF (28 ml. ) are added and the mixture is heated at reflux for 2 hours, cooled to room temperature, and concentrated. The residue is diluted with DCM (600 mL), H2O (500 mL) and NH4OH (100 mL), stirred at rt. for 1 hour and the phases are separated. The aqueous phase is extracted with DCM (2 x 100 mL); The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is triturated with MTBE (150 mL), to provide intermediate 317 (12.796 g, 59% yield) as a beige solid. 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 8.66-8.65 (m, 2 H), 8.43 (d, J = 0.8 Hz, 1 H), 8.30 (d, J = 8.4 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.59 (dd, J = 5.0, 0.6 Hz, 1 H), 5.68 (s, 1 H), 4.19 (dd, J = 11.6, 4.8 Hz, 2H ), 3.99 (t, J = 11.4 Hz, 2H), 2.07-2.01 (m, 1 H), 1.49 (d, J = 13.2 Hz, 1 H).
MS (miz): 333.1 (M + H).
Step 3. 2- (5- (1,3-dioxane-2-yl) pyridin-2-yl) -7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b] pyridine (318) To a suspension of 317 (22.48 g, 67.5 mmol) in phenyl ether (65 ml) is added sodium carbonate (14.32 g, 135 mmol) and 2-fluoro-4-nitrophenol (15.92 g, 101 mmol). The reaction mixture is heated at 180 ° C for 2 hours, cooled to 40 ° C, diluted with DCM (300 ml), stirred at room temperature for 15 minutes and filtered. The filtrate is collected and concentrated to a minimum volume; Et20 (200 ml) is added and the formed suspension is stirred for 30 minutes. The solid material is collected by filtration, to provide intermediate 318 (25.20 g, 55.6 mmol, 82% yield) as a beige solid.
H NMR (400 MHz, DMSO-d6) d (ppm): 8.63-8.62 (m, 2H), 8.48 (dd, J = 10.6, 2.6 Hz, 1 H), 8.43 (s, 1 H), 8.31 (d , J = 8.0 Hz, 1 H), 8.21 (dt, J = 8.8, 1.2 Hz, 1 H), 7.94 (d, J = 8.4, 2.0 Hz, 1 H), 7.71 (t, J = 8.6 Hz, 1 H), 6.98 (d, J = 5.2 Hz, 1 H), 5.67 (s, 1 H), 4.19 (dd, J = 10.8, 5.2 Hz, 2H), 3.98 (td, J = 12.0, 2.0 Hz, 2H ), 2.08-1.99 (m, 1 H), 1.46 (d, J = 13.6 Hz, 1 H).
MS (m / z): 454.2 (M + H).
Step 4. 4- (2- (5- (1 .3-dioxan-2-yl) pyridin-2-yl) thienof3.2-blpyridin-7-yloxy) -3-fluoroaniline (319) Method A To a suspension of 318 (10 g, 22.05 mmol) in EtOH (216 ml) and water (108 ml) is added iron powder (10.47 g, 187 mmol) and ammonium chloride (1015 g, 18.97 mmol). The mixture is refluxed for 30 minutes, filtered hot and the solids washed with ether (200 ml). The filtrate and washings are combined and concentrated to give the title compound 319 (9.62 g, 99% yield) as a beige solid. This material is used in the next step (Scheme 18) without further purification. 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 8.64 (d, J = 2.0 Hz, 1 H), 8. 51 (dd, J = 5.6, 2.0 Hz, 1 H), 8.34 (s, 1 H), 8.28 (dd, J = 8.0, 0.8 Hz, 1 H), 7.93 (dd, J = 8.4, 2.0 Hz, 1 H), 7.13 (t, J = 9.0 Hz, 1 H), 6.61 (dd, J = 5.4, 0.6 Hz, 1 H), 6.54 (dd, J = 13.2, 2.4 Hz, 1 H), 6.46 (ddd, J = 8.8, 2.8, 0.6 Hz, 1 H), 5.67 (s, 1 H), 5.56 (s, 2H), 4.19 (dd, J = 10.6, 5.0 Hz, 2H), 3.98 (td, J = 12.0, 2.5 Hz, 2H), 2.09-1.99 (m, 1 H), 1.49 (dt, J = 13.2, 1.3 Hz, 1 H).
MS (m / z): 424.1 (M + H).
, Method B To a solution of 4-amino-2-fluorophenol (7.42 g, 58.4 mmol) in DMSO (65 mL) is added potassium tert-butoxide (7.75 g, 69.0 mmol). After 30 minutes, intermediate 317 (17.67 g, 53.1 mmol) is added and the reaction mixture is heated at 100 ° C for 1.5 hours, cooled to room temperature, poured into water (300 ml) at 40-45 ° C and stirred for 30 minutes. The solid is collected by filtration, washed with water (2 x 30 ml) and dried for 2 hours. This material is triturated with ether (60 ml), to give the title compound 319 (19.80 g, 88% yield) as a brown solid.
MS (m / z): 424.1 (M + H).
SCHEME 18 EXAMPLE 203 1 - . 1 - (4- (2- (5-5,8,11,14-Tetraoxa-2-azapentadecylpyridin-2-yl) thienof312-blpyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (323) Step 1: 1- (4- (2- (5- (1,3-dioxane-2-yl) pyridin-2-yl) thieno [3,2-blpyridin-7-yloxy) -3-fluorophenyl) -3 -cyclopropylurea (320) A 100 ml round bottom flask is charged with 319 (0.55 g, 1.3 mmol) and DIPEA (0.91 ml, 5.2 mmol) in dry tetrahydrofuran (55 ml) to give a colorless solution. The reaction mixture is cooled to 0 ° C and then triphosgene (0.154 g, 0.520 mmol) is added. The reaction mixture is stirred for 1 hour at 0 ° C and then cyclopropylamine (1.8 ml, 26 mmol) is added. Finally, the reaction mixture is stirred at room temperature for 3 hours then concentrated. The residue is partitioned between water and ethyl acetate, resulting in the formation of a white, thick solid. This is isolated by suction filtration, rinsed with water and ethyl acetate, and dried in vacuo to give the crude 320 (0.65 g, 1.2 mmol, 99% yield) which is used without further purification.
MS: 507.2 (M + H).
Step 2: 1-Cyclopropyl-3- (3-fluoro-4- (2- (5-formylpyridin-2-yl) thieno [3,2-blpyridin-7-yloxy) phenyl) urea (321) A suspension of 320 (0.65 g, 1.3 mmol) in 5: 2: 1 acetone / water / TFA (100 mL) is heated at reflux for 6 hours. The mixture is then cooled and concentrated. The resulting solid residue is suspended in water, isolated by suction filtration, washed with ethyl acetate and dried under vacuum to give 321 (0.49 g, 1.1 mmol, 85% yield) which is used without further purification in the next stage.
MS: 449.0 (M + H).
Step 3. 2,5,8,11-Tetraoxatridecan-13-amine (322) Tetraethylene glycol monomethyl ether (10.0 ml, 47.5 mmol), phthalimide (7.20 g, 48.9 mmol) and triphenylphosphine (12.8 g, 48.8 mmol) is suspended in dry tetrahydrofuran (200 ml) to obtain a colorless suspension. Diethyl azodicarboxylate (8.0 ml, 50.5 mmol) is added dropwise with a syringe, and the mixture is stirred at room temperature for 18 hours. Then ethanol (50 ml) is added, the mixture is stirred for another 30 minutes and then concentrated under reduced pressure. The residue is dissolved in 1: 1 ethyl acetate / hexanes (100 ml), stirred at 0 ° C for 2 hours, and the resulting white precipitate is removed by suction filtration. The filtrate is concentrated (13.5 g, 40.0 mmol, 84% yield) and used in the next step without further purification.
The above crude product is dissolved in ethanol (100 ml) to give a colorless solution. Hydrazine hydrate (2.3 ml, 40 mmol) is added and the mixture is refluxed for 4 hours. After cooling, concentrated HCl (10.0 ml) is added, and the mixture refluxes for an additional 1 hour. Then it is allowed to cool to room temperature, the white precipitate is removed by filtration by suction, and the filtrate is concentrated. The residue is divided between water and diethyl ether. The aqueous phase is extracted with ether (organic phase, which mostly contains PPh3 by EM, is discarded), then basified with 3M NaOH (50 ml) at pH = 13. The aqueous phase is saturated with sodium chloride and extract several times with dichloromethane (-10 x 50 mL). The organic extract is dried (MgSO4) and concentrated to yield 322 (7.0 g, 33.8 mmol, 84% yield, 71% in 2 steps). This is used without further purification in the next step.
MS (m + 1) = 208.1.
Step 4: 1 - (4- (2- (5-5,8,11,14-Tetraoxa-2-azapentadecylpyridin-2-yl) thienof3,2-blpyridin-7-yloxy) -3-fluorophenyl) -3- cyclopropylurea (323) To a suspension of carboxaldehyde 321 (0.45 g, 1.0 mmol) and amine 322 (1.4 g, 6.75 mmol) in dichloromethane (75 ml) is added acetic acid (0.12 ml, 2.0 mmol). The reaction mixture is stirred for 1 hour, and then sodium triacetoxyborohydride (0.64 g, 3.0 mmol) is added and the resulting mixture is stirred for 18 hours. The mixture is then partitioned between water and dichloromethane, washed with 1 M NaOH and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue is purified by Gilson reverse phase HPLC (35-75% MeOH / H2O, Aquasil CiB, 30 minutes) and lyophilized. The purified product (containing a little formic acid from the HPLC) is partitioned between hot dichloromethane and 1 M NaOH. The organic phase is dried (MgSO4), filtered and concentrated to give the title compound 323 (0.264 g, 0.413 mmol, 41.1% yield). 1 H NMR (DMSO-d 6) 6 (ppm) 1 H: 8.80 (s, 1 H); 8.57 (s, 1 H); 8.51 (d, J = 5.5, 1 H); 8.31 (s, 1 H); 8.23 (d, J = 8.0, 1 H) 7.89 (dd, J = 8.0, 1.5, 1 H); 7.73 (dd, J = 1 3.5, 2.2, 1 H); 7.38 (t, J = 9.0, 1 H) 7.20 (d, J = 8.2, 1 H); 6.67 (d, J = 2.7, 1 H); 6.64 (d, J = 5.5, 1 H); 3.78 (s, 2H); 3.56-45 (m, 12H); 3.41 (t, J = 5.7, 2H); 3.21 (s, 3H); 2.66 (d, J = 5.7, 2H); 2.58-2.51 (m, 1 H); 0.66-0.62 (m, 2H) ¡0.44-0.41 (m, 2H).
LREM: 640.5 (M + H).
SCHEME 19 324: example 204 EXAMPLE 204 Acid (S) -2-amino-6 - ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thienor3.2-b1pyridin-2-yl) pyridin-3-yl) methylamino hexanoic) Í324J To a suspension of 321 (0.26 g, 0.58 mmol) and N-Boc-lysine (1.1 g, 4.6 mmol) in dichloromethane (75 ml) and acetic acid (0.066 ml, 1.2 mmol) is added. The reaction mixture is stirred for 1 hour, then sodium triacetoxyborohydride (0.37 g, 1.7 mmol) is added and the mixture The resulting mixture is stirred for 18 hours. The mixture is then partitioned between water and dichloromethane, and the precipitated solid removed by suction filtration through celite. The product is mainly in the filter cake of solids, so it is solubilized by washing with 1: 1 dichloromethane / methanol. This solution is concentrated and the residue is purified by Gilson reverse phase HPLC (35-75% MeOH / H2O, Aquasil C18, 30 min) and lyophilized to give the BOC-protected product. This is dissolved in dichloromethane (75 ml) and trifluoroacetic acid (3 ml), and stirred at room temperature for 3 hours. The mixture is concentrated and the residue is purified by Gilson reverse phase HPLC (35-75% MeOH / H20, Aquasil C18, 30 min) and lyophilized to give the title compound 324 (44 mg, 69% yield). 1 H NMR (DMSO-de) 6 (ppm) 1 H: 9.02 (s, 1 H); 8.66 (s, 1 H); 8.53 (d, J = 5.3, 1 H); 8.35 (s, 1 H); 8.28 (d, J = 8.4, 1 H) 7.98 (d, J = 6.3, 1 H); 7.72 (dd, J = 13.5, 2.3, 1 H); 7.37 (t, J = 9.0, 1 H); 7.21 (d, J = 10.0, 1 H); 6.89 (s, 1 H); 6.68 (d, J = 5.3, 1 H); 4.00 (s, 2H); 2.75-2.70 (m, 2H) 2.55-2.52 (m, 1 H); 2.45 (m, 1 H); 1.70-1.30 (m, 6H); 0.67-0.62 (m, 2H); 0.44-0.40 (m, 2H).
LREM: 579.5 (M + H).
Faith; NH4CI; eOH / H20 329 330 331: example 205 EXAMPLE 205 1-Cyclopropyl-3- (3-fluoro-4- (2- (5 - ((2- (2-methoxyethoxy) ethylamino) methyl) pyridin-2-yl) thieno [3,2-b] pyridine-7- iloxy) phenyl) urea Step 1: 6- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-blpyridin-2-D-nicotinaldehyde (325) A suspension of 318 (2.64 g, 5.82 mmol) in 80% aqueous acetic acid (42 ml) is heated at 90 ° C for 18 hours. The reaction mixture is cooled to room temperature and diluted with water. The resulting precipitate is collected by suction filtration. The solid is transferred to a round bottom flask, the remaining water is removed by azeotropic distillation with toluene (4 times), and the dry solid under vacuum produces 325 (1.76 g, 76%). .
LREM: (M + H) 396.3 Step 2: 2- (2-methoxyethoxy) ethanamine (326) Diethylene glycol monomethyl ether (9.8 ml, 83 mmol), phthalimide (14.7 g, 100 mmol), and triphenylphosphine (26.2 g, 100 mmol) is suspended in dry tetrahydrofuran (200 ml) to obtain a colorless suspension (see scheme 18, step 3). Dietl azodicarboxylate (15.8 ml, 100 mmol) is added dropwise with a syringe, and the mixture is stirred at room temperature for 18 hours. Then ethanol (50 ml) is added, the mixture is stirred for another 30 minutes and then concentrated under reduced pressure. The residue is dissolved in ethyl acetate / hexanes 1: 1 (100 ml), stirred at 0 ° C for 2 hours, and the resulting white precipitate is removed by suction filtration. The filtrate is concentrated and used in the next step without further purification.
The above crude product is dissolved in ethanol (200 ml) to give a colorless solution. Hydrazine hydrate (5.1 ml, 104 mmol) is added and the mixture is refluxed for 4 hours. It is then cooled, concentrated HCl (16 ml) is added, and the mixture is refluxed for an additional 1 hour. Then it is cooled to room temperature, the white precipitate is removed by filtration with suction, and the filtrate is concentrated. The residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate (organic phase, which mostly contains PPhaO with MS, is discarded), then basified with 3M NaOH (50 ml) at pH = 13. The aqueous phase is saturated with sodium chloride and extracted several times with dichloromethane (-10 x 50 ml). The organic extract is dried (MgSO4) and concentrated to yield 326 (6.6 g, 56 mmol, 67% yield in 2 steps). This is used without further purification in a subsequent reaction.
MS (m + I) = 120.2.
Step 3: N - ((6- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-blpyridin-2-yl) pyridin-3-yl) methyl) -2- (2-methoxyethoxy) Ethanamine (327) A suspension of carbaldehyde 325 (0.50 g, 1 .3 mmol), amine 326 (0.30 g, 2.5 mmol) and acetic acid (0.14 mL, 2.5 mmol) in dichloromethane (20 mL) is stirred for 1 hour at room temperature. Then sodium triacetoxyborohydride (0.80 g, 3.8 mmol) is added and stirred at room temperature for 16 hours. An additional amount of sodium triacetoxyborohydride (1.0 g) is then added and the stirring is continued for 2 hours. The reaction mixture is partitioned between dichloromethane and 1 N NaOH. The yellow suspension is filtered off and rinsed with dichloromethane and 1 N NaOH. The organic extract is dried over anhydrous sodium sulfate, filtered and concentrated. The organic residue is purified with Biotage (linear gradient 0-20%, methanol / dichloromethane, column 100g Snap) to produce 327 (280 mg, 0.562 mmol, 44%) as a yellow solid.
LREM: (M + H): 499.4.
Step 4: (6- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b1pyridin-2-yl) pyridin-3-yl) methyl (2- (2-methoxyethoxy) ethyl) carbamate tere -butyl (328) To compound 327 (0.28 g, 0.56 mmol) in dichloromethane (100 ml) at room temperature is added (0.25 ml, 1.7 mmol), DMAP (0.017 g, 0.14 mmol) and Boc2O (0.26 g, 1.1 mmol). The reaction mixture is stirred at room temperature for 2 hours, then the mixture is washed sequentially with water, saturated ammonium chloride, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography (ethyl acetate) to yield compound 328 (0.20 g, 60% yield).
LREM: (M + H): 599.5.
Step 5: (6- (7- (4-amino-2-fluorophenoxy) thienof3.2-b1pyridin-2-yl) pyridin-3-yl) methyl (2- (2-methoxyethoxy) ethyl) tertiary carbamate -butyl (329) To the nitro compound 328 (0.20 g, 0.33 mmol) in MeOH (75 ml) is added iron powder (0.37 g, 6.7 mmol) and ammonium chloride (0.089 g, 1.7 mmol) in water (5 ml). The resulting mixture is refluxed for 4 hours, then cooled, filtered through celite and concentrated. The residue is partitioned between ethyl acetate and water, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The product 329 (0.18 g, 95%) is used crude in the next stage.
LREM: (M + H): 569.5.
Step 6: (6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b | pyridin-2-yl) pyridin-3-yl) methyl (2- (2-methoxyethoxy) Ethyl) tert-butyl carbamate (330) To amine 330 (0.17 g, 0.30 mmol) and DIPEA (0.16 mL, 0.12 g, 0.90 mmol) in tetrahydrofuran (25 mL) is added at 0 ° C triphosgene (0.035 g, 0.12 mmol) and the resulting solution is stirred for 1 hour. hour at 0 ° C. Cyclopropylamine (0.26 g, 4.6 mmol) is added and the mixture is warmed to room temperature and stirred for 18 hours, then concentrated under reduced pressure. The residue is partitioned between dichloromethane and water, the organic phase is washed with saturated NH 4 Cl (aC) and brine, dried over MgSO 4, it is filtered and concentrated, yielding 330 crude (0.15 g, 77% yield). LREM: (M + H): 652.6.
Step 7: Cyclopropyl-3- (3-fluoro-4- (2- (5 - ((2- (2-methoxyethoxy) ethylamino) methyl) pyridin-2-yl) thieno [3,2-blpyridin-7] -iloxy) phenyl) urea (331) Compound 330 (0.15 g, 0.23 mmol) is dissolved in dichloromethane (20 ml) and trifluoroacetic acid (0.9 ml) and the reaction mixture is stirred for 12 hours at room temperature. The mixture is concentrated and the residue is purified by Gilson reverse phase HPLC (40-80% MeOH / H20, Aquasil C 8, 30 minutes) and lyophilized. The purified product (containing a little formic acid of HPLC) is divided between hot dichloromethane and 1 M NaOH. The organic phase is dried (MgSO 4), filtered and concentrated to give the title compound 331 (0.110 g, 72 % yield) (a mono-TFA salt despite treatment with NaOH). 1 H NMR (DMSO-de) 6 (ppm) 1 H: 8.84 (s, 1 H); 8.65 (d, J = 1 .3, 1 H); 8.53 (d, J = 5.5, 1 H); 8.37 (s, 1 H); 8.30 (d, J = 8.2, 1 H); 7.99 (dd, J = 8 2, 2.0, 1 H); 7.73 (dd, J = 13.7, 2.5, 1 H); 7.38 (t, J = 9.0, 1 H); 7.22-7.18 (m, 1 H); 6.68-6.64 (m, 2H); 4.03 (s, 2H); 3.60-3.52 (m, 4H); 3.48-3.44 (m, 2H); 3.25 (s, 3H) 2.92-2.88 (m, 2H); 2.55 (septet, J = 3.1, 1 H); 0.69-0.62 (m, 2H); 0.44-0.40 (m, 2H).
LREM: (M + H): 552.5.
SCHEME 21 332: example 206 333: example 207 EXAMPLES 206 and 207 4 - ((6- (7- (4- (3-Cyclopropylureido) -2-fluorophenoxy) thienor3,2-b1pyridin-2-yl) pyridin-3-yl) methylamino) butanoic acid (332), and 1 -cyclopropyl-3- (3-fluoro-4- (2- (5 - ((2-oxopyrrolidin-1-yl) methyl) pyridin-2-yl) thienor3,2-b1pyridin-7-yloxy) phenylurea (333) To a suspension of carbaldehyde 321 (0.20 g, 0.45 mmol) and 4-aminobutytic acid (1.0 g, 9.7 mmol) in dichloromethane (75 ml) and acetic acid (0.051 ml, 0.89 mmol) is added. The reaction mixture is stirred for 1 hour, then sodium triacetoxyborohydride (0.38 g, 1.8 mmol) is added and the resulting mixture is stirred for 18 hours. The mixture is partitioned between water and dichloromethane, and the precipitated solid is removed by suction filtration through celite. EM analysis indicates that the cyclized product 333 is in the filtrate, while the acid product 332 is mostly in the solid filter cake. The organic phase from the filtrate is concentrated and the residue is purified by silica gel chromatography (10% MeOH / ethyl acetate) to provide 333 purified (35 mg, 15% yield). The product in the celite filter cake is solubilized by washing with 1: 1 dichloromethane / methanol. This solution is concentrated and the residue is purified by Gilson reverse phase HPLC (35-75% MeOH / h <0>, Aquasil Ci <8>, 30 minutes) and lyophilized to give acid 332 (44 mg, 69% yield). Characterization of compounds 332 and 333 is provided below.
Compound 332 (example 206): 1 H NMR (DMSO-d 6) or (ppm) 1 H: 9.23 (s, 1 H); 8.58 (s, 1 H); 8.51 (d, J = 5 4, 1 H); 8.36 (s, 1 H); 8.32 (s, 1 H); 8.24 (d, J = 8.2, 1 H); 7.91 (dd, J = 8.4, 2.0, 1 H); 7.74 (dd, J = 13.7, 2.3, 1 H); 7.37 (t, J = 9.0, 1 H); 7.22 (d, J = 9.0, 1 H); 6.63 (d, J = 5.3, 1 H); 3.79 (s, 2H) 2.56 (t, J = 5.1, 2H); 2.47-2.43 (m, 1 H); 2.27 (t, J = 7.2, 2H) 1.65 (quintuplet, J = 6.7, 2H); 0.66-0.61 (m, 2H); 0.44-0.40 (m, 2H).
LREM: (M + H) 536.4.
Compound 333 (example 207): 1 H NMR (DMSO-d 6) or (ppm) 1 H: 8.76 (s, 1 H); 8.52 (s, 1 H) 8.52 (d, J = 5.5, 1 H); 8.35 (s, 1 H); 8.26 (d, J = 8.2, 1 H); 7.79 (dd, J = 8.2, 2.1, 1 H); 7.73 (dd, J = 13.5, 2.5, 1 H); 7.38 (t, J = 9.2, 1 H); 7.20 (d, J = 8.4, 1 H); 6.65 (d, J = 5.3, 1 H); 6.62 (s, 1 H); 4.46 (s, 2H); 3.30-3.20 (t, 2H, darkened by peak water?); 2.55 (quintuplet, J = 3.3, 1 H); 2.31 (t, J = 7.8, 2H); 1 .95 (quintuplet, J = 7.6, 2H); 0.67-0.62 (m, 2H); 0.45-0.40 (m, LREM: (M + H) 518.4 SCHEME 22 335: example 209 EXAMPLES 208 and 209 Step 1: (S) -1-cyclopropyl-3- (3-fluoro-4- (2- (5 - ((1-methoxypropan-2-ylammon) methyl) -pyridin-2-yl) thieno [3 , 2-b1-pyridin-7-yloxy) phenyl) urea (334) To a stirred suspension of carbaldehyde 321 (336 mg, 0.749 mmol), (S) -1-methoxy-2-aminopropane (200 mg, 2248 mmol) and acetic acid (68 mg, 1124 mmol) in DCM (20 mL) a Room temperature under nitrogen is added NaBH (OAc) 3 (418 mg, 1873 mmol). The reaction mixture is stirred at room temperature overnight and quenched with a 1.0% HCl solution. The layers are separated, the aqueous layer is collected, washed twice with DCM and basified with 4N NaOH (pH 12) to form a suspension which is stirred for 30 minutes. The solid is collected by filtration, dried with water and dried with air and purified by flash column chromatography on silica gel (eluent 2% ammonium hydroxide in MeOH / DCM: 10/90) to produce the title 334 (182 mg, 0.35 mmol, 46% yield) as a yellow fluffy solid.
H NMR (400 MHz, DMSO-d6) d (ppm): 8.71 (s, 1 H), 8.58 (d, J = 1.6 Hz, 1 H), 8.51 (d, J = 5.5 Hz, 1 H) , 8.31 (s, 1 H), 8.23 (d, J = 8.2 Hz, 1 H), 7.91 (dd, J = 8.2, 2.2 Hz, 1 H), 7.73 (dd, J = 13.6, 2.4 Hz, 1 H ), 7.38 (t, J = 9.0 Hz, 1 H), 7.23-7.17 (m, 1 H), 6.64 (d, J = 5.5 Hz, 1 H), 6.57 (bd, J = 2.7 Hz, 1 H) , 3.84 (d, J = 14.5 Hz, 1 H), 3.78 (d, J = 14.5 Hz, 1 H), 3.27 (d, J = 9.4, 6.3 Hz, 1 H), 3.24 (s, 3 H), 3.19 (dd, J = 9.2, 5.5 Hz, 1 H), 2.81 -2.71 (m, 1 H), 2.59-2.51 (m, 1 H), 2.36-2.10 (m, 1 H), 0.98 (d, J = 6.3 Hz, 3H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H).
MS (m / z): 522.4 (M + H).
Step 2j (S) -N - ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b1-pyridin-2-yl) pyridin-3-yl) methyl) -N - (1-methoxypropan-2-D-acetamide (335) A suspension of urea 334 (66 mg, 0.127 mmol) in acetic anhydride (2 mL) is stirred at room temperature for 2 days. The reaction mixture is quenched by the addition of methanol and water, and divided with AcOEt. After separation, the organic layer is collected, washed with water, 1 N NaOH (x4) water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is purified by flash column chromatography on silica gel (eluent 2% ammonium hydroxide in MeOH / DCM: 05/90 to 10/90) to yield the title compound 335 (46 mg, 0.08 mmol, 64%). % yield) as a whitish fluffy solid. 1 H NMR (400 MHz, DMSO-d 6) d (ppm): mixture of rotamers, 8.70 (s, 1 H), 8.58-8.48 (m, 2 H), 8.34 and 8.30 (2 s, 1 H), 8.27 and 8.19 ( 2d, J = 8.3 Hz, 1 H), 7.85-7.69 (m, 2H), 7.38 (t, J = 9.0 Hz, 1 H), 7.20 (bd, J = 9.0 Hz, 1 H), 6.67-6.54 ( m, 2H), 4.74-4.16 (m, 3H), 3.41 -3.22 (m, 2H), 3.15 and 3.13 (2s, 3H), 2.59-2.52 (m, 1 H), 2.16 and 1.96 (2s, 3H) , 1.09 and 1 .04 (2d, J = 6.9 Hz, 3H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H).
MS (m / z): 564.4 (M + H).
SCHEME 23 EXAMPLE 210 N- (3-Fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) pyridin-2-intienor3,2-b] pyridin-7-yloxy) phenyl) cyclopropanecarboxamide (337) Step V. (6- (4- (Cyclopropanecarboxamido) -2-fluorophenoxy) thieno [3,2-blpyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) tert-butyl carbamate (336) To a solution of aniline 126 (200 mg, 0.36 mmol) in DCM (10 mL) under nitrogen at 0 ° C is added DIPEA (127 μ ?, 0.72 mmol) and cyclopropylcarbonyl chloride (50 μ ?, 0.54 mmol). The reaction mixture is allowed to warm to room temperature slowly and is stirred overnight at room temperature. The reaction mixture is diluted in AcOEt, and washed successively with saturated aqueous solution of ammonium chloride (x4), 1 N NaOH (x2), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrate The crude residue is co-precipitated at a minimum of AcOEt in hexanes. The solid is collected by filtration, rinsed with hexanes, dried with air and dried under high vacuum to yield the title compound A (quantitative yield) as a pale brown solid.
MS (m / z): 593.4 (M + H).
Step 2: N- (3-Fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) pyridin-2-yl) thienof3,2-b1-pyridin-7-yloxy) phenyl) cyclopropanecarboxamide (337) To a solution of amide 336 (215 mg, crude mixture) in DCM (10 mL) is added TFA (2 mL). The reaction mixture is stirred at room temperature for 2 hours, concentrated, partitioned between water and AcOEt, and basified with 1 N NaOH solution. After layer separation, the organic layer is collected, washed with NaOH 1 N (x2), water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (eluent 2% ammonium hydroxide in MeOH / DCM: 05/95 to 15/95) to yield the title compound 336 (87 mg, 0.177 mmol, 48 % yield) as a sticky salmon solid.
H NMR (400 MHz, D SO-d6) d (ppm): 10.57 (s, 1 H), 8.57 (d, J = 1.6, 1 H), 8.52 (d, J = 5.5 Hz, 1 H), 8.32 (s, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 7.93-7.83 (m, 2H), 7.47 (t, J = 8.9 Hz, 1 H), 7.41 (dd) , J = 8.9, 2.0, 1 H), 6.66 (d, J = 5.3 Hz, 1 H), 3.78 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H), 2.66 (t, J = 5.7 Hz, 2H), 1.79 (quint., J = 6.2 ??, 1 H), 0.90-0.80 (m, 4H), an NH is lost.
MS (m / z): 493.4 (M + H).
SCHEME 24 THF 339 34 Example 211 341: Example 212 EXAMPLE 340 AND 341 (6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thienoi3,2-blpyrdin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate I340) and (R ) -2-amino-N - ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thienor3,2-blpyridin-2-yl) pyridin-3-yl) metin-N- (2 -methoxyethyl) -3-methylbutanamide (341) Stage 1: (6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b1pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate of tere- Butyl (338) Amine 126 (0.24 g, 0.46 mmol) in tetrahydrofuran (60 ml) at 0 ° C is added with triphosgene (0.054 g, 0.18 mmol) and the resulting solution is stirred for 1 hour at 0 ° C. DIPEA (0.40 ml, 0. 30 g, 2.3 mmol) and cyclopropylamine (0.26 g, 4.6 mmol) and the mixture is warmed to room temperature and stirred for 3 hours, then concentrated under reduced pressure. The residue is partitioned between dichloromethane and water, the organic phase is collected, washed with saturated NH 4 Cl (aq), and brine, dried over MgSO 4, filtered and concentrated. The residue is purified by flash chromatography on silica gel (ethyl acetate to 5% methanol / ethyl acetate), yielding 338 (0.19 g, 67% yield).
MS (m / z) 608.4 (M + H).
Step 2j 1-Cyclopropyl-3- (3-fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) pyridin-2-yl) thienof3,2-blpyridin-7-yloxy) phenyl) urea (339 ) To 338 (0.19 g, 0.31 mmol) in dichloromethane (40 mL) is added TFA (3 mL). The solution is stirred for 6 hours, then concentrated. The residue is partitioned between 98: 2 dichloromethane / methanol and 1 M NaOH (aq) mixture, washed with brine, dried over MgSO4, filtered and concentrated. The resulting oil is triturated with diethyl ether and ethyl acetate yields 339 (0.13 g, 82% yield). 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 1 H: 8.80 (s, 1 H); 8.57 (s, 1 H); 8.51 (d, J = 5.5, 1 H); 8.31 (s, 1 H); 8.23 (d, J = 8.0, 1 H); 7.89 (dd, J = 8.0, 1.5, 1 H); 7.73 (dd, J = 13.5, 2.2, 1 H); 7.38 (t, J = 9.0, 1 H); 7.20 (d, J = 8.2, 1 H); 6.66-6.62 (m, 2H); 3.78 (s, 2H) 3.41 (t, J = 5.7, 2H); 3.24 (s, 3H); 2.65 (d, J = 5.7, 2H); 2.57-2.51 (m, 1 H), 0.66-0.62 (m, 2H); 0.44-0.41 (m, 2H).
MS (m / z): 508.3 (M + H).
Step 3: (6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-blpyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate (340) To a solution of compound 339 (220 mg, 0.433 mmol) and methyl chloroformate (50.2 μ ?, 0.65 mmol) in THF (4 mL) is added DIPEA (227 μ ?, 1.30 mmol) and the mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure, the residue is triturated with MeOH and the solid suspension is collected by filtration and purified via Biotage (linear gradient 0-20% methanol / dichloromethane; Snap column 25 g) to produce compound 340 ( 123.1 mg, 0.218 mmol, 50.2% yield) as a beige solid. 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 8.70 (s, 1 H), 8.56-8.50 (m, 2H), 8.33 (s, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.84-7.77 (m, 1 H), 7.73 (dd, J = 13.6, 2.4 Hz, 1 H), 7.38 (t, J = 9.2 Hz, 1 H), 7.20 (dd, J = 8.8, 1.2 Hz, 1 H), 6.65 (d, J = 5.6 Hz, 1 H), 6.56 (d, J = 2.8 Hz, 1 H), 4.54 (s, 2H), 3.64 (s, 2H), 3.44 (s, 3H), 3.22 (s, 2H), 2.59-2.51 (m, 1 H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H).
MS (m / z): 566.4 (M + H).
Step 4: (R) -2-amino-N - ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thienof3,2-blpyrdin-2-yl) pyridin-3-yl ) methyl) -N- (2-methoxyethyl) -3-methylbutanamide (341) To a solution of 339 (48 mg, 0.095 mmol), N-Boc-valine (41 mg, 0.19 mmol), and DIPEA (0.083 mL, 0.47 mmol) in DMF (20 mL) is added HATU (90 mg, 0.236 mmol). ). The resulting solution is stirred at room temperature for 3 hours. The reaction mixture is partitioned between ethyl acetate and water, washed with 1 M HCl and brine, dried (MgSO 4), filtered and concentrated to yield the crude BOC-protected product. This material is dissolved in dichloromethane (75 ml) and trifluoroacetic acid (3 ml) and stirred at room temperature for 3 hours. The mixture is then concentrated and the residue is purified by reverse phase HPLC (35-95% MeOH / (H20, Aquasil Ci8, 30 minutes) and lyophilized The residue (containing some formic acid HPLC) is divided. between dichloromethane and 1 M NaOH. The organic phase is dried (MgSO) filtered and concentrated to provide 341 (18 mg, 50% yield) as a 7: 3 mixture of rotamers per 1 H NMR. 1 H NMR (DMSO-d 6) d (ppm) 1 H. 8.73 (s, 1 H); 8.57-8.51 (m, 2H); 8.36 (s, 0.3H); 8.32 (s, 0.7H); 8.29-8.24 (m, 1 H) 7.84-7.71 (m, 2H); 7.38 (t, J = 8.8, 1 H); 7.21 (d, J = 8.3, 1 H); 6.66-6.64 (m, 1 H); 6.59 (s, 1 H) 4.90 (d, J = 17.6, 0.3H); 4.73 (d, J = 15.6, 0.7H); 4.64 (d, J = 17.1, 0.3H); 4.53 (d, J = 15.6, 0.7H); 3.73-3.39 (m, 5H); 3.25 (s, 2.2H); 3.22 (s, 1 .1 H); 2.58-2.52 (m, 1 H); 1.80-1.70 (m, 1 H); 0.89-0.84 (m, 6H); 0.68-0.64 (m, 2H); 0.45-0.41 (m, 2H).
LREM: (M + H) 607.5.
SCHEME 25 EXAMPLE 213 AND 214 N1- (3-fluoro ^ - (2- (5 - ((2-methoxyethylamino) methyl) pyridin-2-yl) thienof3,2-blpyridin-7-yloxy) phenyl) -N3- (3-methylsulfonyl) phenyl) malonamide (345 and N-3-fluoro ^ - (2- (5 - ((N- (2-methoxyethyl) acetamide) methyl) pyridin-2-yl) thienor 3,2-blpyridin-7-yloxy) phenyl) -N 3 - (3-methylsulfonyl) phenyl) malonamide (346) Step 1j 3- (4- (2- (5- (tert-Butoxycarbonyl (2-methoxyethoamino) methylpyridin-2-yl-thienor-3-bp-pyridin-7-yloxy) -3-fluorophenylamino) -3-oxopropanoate methyl (342) To a solution of compound 126 (480 mg, 0.915 mmol) and DIPEA (479 μ ?, 2.74 mmol) in DCM (9 ml) at room temperature is added methyl chloride (196 μl, 1.83 mmol). The mixture is stirred at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride is added and the aqueous phase is extracted twice with DCM. The combined organic layers are dried over anhydrous sodium sulfate and concentrated. The residue is purified via Biotage (linear gradient 0-20% methanol / dichloromethane; Snap column 50 g) to yield compound 342 (540 mg, 0.86 mmol, 94% yield) as a yellow oil.
MS (m / z): 625.5 (M + H).
Step 2: 3- (4- (2- (5 - ((tert-butoxycarbonyl) amino) methyl) pyridin-2-yl) thieno [3,2-blpyridin-7-yloxy) -3-fluorophenylamino -3-oxopropanoic (343) To a solution of compound 342 (540 mg, 0.864 mmol) in THF (12 mL) and water (6 mL) is added LiOH monohydrate ((363 mg, 8.64 mmol) .The mixture is stirred 48 hours at room temperature and THF The mixture is stirred under reduced pressure for 48 hours at room temperature and THF is removed under reduced pressure.The aqueous solution is diluted with water (10 ml) and acidified to pH 4 using 1 N HCl. the precipitate is dried under high vacuum to yield compound 343 (485 mg, 0.79 mmol, 92% yield) as a beige solid.
MS (m / z): 61.1.5 (M + H).
Step 3 and 4 N1- (3-fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) pyridin-2-yl) thienof3,2-blpyridin-7-yl (methylsulfonyl) phenyl) malonamide (345) To a solution of compound 343 (120 mg, 0.197 mmol), 3-methylsulfonylaniline hydrochloride (82 mg, 0.393 mmol) and DIPEA (172 μ ?, 0.983 mmol) in DMF (4 mL) was added BOP ractive (261 mL, 0.59). mmol) and the mixture is stirred at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride is added and the aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The residue is purified via Biotage (linear gradient 0-20%, methanol / dichloromethane, Snap column 25 g) to produce compound 344 as yellow solid (not characterized) which is dissolved in DCM (10 ml) and treated with TFA ( 4.5 mL, 59 mmol). The mixture is stirred for 18 hours at room temperature. The solvent is removed under reduced pressure, the residue is diluted with ethyl acetate and the organic layer is extracted with 1 N NaOH. The aqueous phase is extracted three times with ethyl acetate and the combined organic layers are concentrated. The residue is purified via Biotage (linear gradient 0-30%, methanol / dichloromethane, Snap column 50 g) to yield compound 345 (39 mg, 0.059 mmol, 29.9% yield) as a beige solid. 1 H NMR (400 MHz, DMSO-d 6) d (ppm): 10.65 (s, 1 H), 10.61 (s, 1 H), 8.57 (d, J = 1.6 Hz, 1 H), 8.52 (d, J = 5.2 Hz, 1 H), 8.33 (s, 1 H), 8.28 (s, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 7.92-7.85 (m, 3 H), 7.66-7.60 (m , 2H), 7.51 (t, J = 8.8 Hz, 1 H), 7.45 (dd, J = 9.2, 1.6 Hz, 1 H), 6.68 (dd, J = 5.2, 0.8 Hz, 1 H), 3.79 (s) , 2H), 3.57 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H), 3.21 (s, 3H), 2.66 (t, J = 5.6 Hz, 2H).
MS (m / z): 664.5 (M + H).
Step 5 N1- (3-Fluoro-4- (2- (5 - ((N- (2-methoxyethyl) acetamido) methyl) pyridin-2-yl) thienol [3,2-b1pyridin-7-yloxy) phen (methylsulfonyl) phenyl) malonamide (346) A solution of compound 345 (18.5 mg, 0.028 mmol) in acetic anhydride (1.31 ml, 13.9 mmol) is stirred at room temperature for 60 hours. The solvent is removed under reduced pressure and the residue is triturated with water for 3 hours. The solid suspension is filtered, the precipitate is rinsed with water and dried under high vacuum to yield compound 346 (6.4 mg, 9.07 μ? T ??, 32.5%) as a beige solid. 1 H NMR (400 MHz, DMSO-d 6) d (ppm): mixture rotamers, 1 0.64 (s, 1 H), 10.60 (s, 1 H), 8.55-8.49 (m, 2 H), 8.38-8.21 (m, 3H), 7.91-7.86 (m, 2H), 7.78 (td, J = 8.8, 2.0 Hz, 1 H), 7.66-7.60 (m, 2H), 7.51 (t, J = 8.8 Hz, 1 H), 7.44 (dd, J = 9.2, 1.6 Hz, 1 H), 6.71 -6.67 (m, 1 H), 4.71 and 4.59 (2s, 2H), 3.58-3.23 (m, 14H), 3.21 (s, 3H), 2.13 and 2.05 (2s, 3H).
MS (m / z): 706.5 (M + H).
SCHEME 26 do not N - ((2- (7- (4- (3-cyclopropylidene) -2-fluorophenoxy) thienof3,2-b1-pyridin-2-yl) -1-methyl-1 H-imidazol-5-yl) methyl) -N- (2-methoxyethyl) methanesulfonamido (349) Step 1: (2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thienof3.2-b1-pyridin-2-yl) -1-methyl-H-imidazol-5-yl) methyl (2-methoxyethyl) tere-butyl carbamate (347) To a solution of the aniline 46 (400 mg, 0.758 mmol) is added triphosgene (1125 mg, 5 eq, 3.79 mmol) and Pr2NEt (490 mg, 5 eq 3.79 mmol) and the reaction mixture is stirred at room temperature for one hour. Cyclopropylamine (6103 mg, 141 eq 107 mmol) is added and the reaction mixture is stirred at room temperature overnight. The mixture is concentrated, then diluted with DCM and washed with water. The organic phase is collected, dried over Na 2 SO 4, filtered and evaporated. The residue is purified by column chromatography (eluent 20% MeOH in EtOAc) to yield the desired compound 347 as a yellow oil (426 mg, 92% yield).
MS (m / z) = 61 1.4 (M + H) Step 2j 1-cyclopropyl-3- (3-fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) -1-methyl-H-imidazol-2-yl) thieno [3,2-b1pyridin- 7-yloxy) phenyl urea (348) To a solution of 347 (426 mg, 0.698 mmol) in DCM (10 mL) is added HCI in dioxane (0.7 mL, 4.01 eq., 2.80 mmol, 4M in dioxane) and the reaction mixture is stirred at room temperature for 3 hours. hours. The mixture is diluted with water and solid NaHCO3 is added. The reaction mixture is extracted well with EtOAc then the organic phase is collected, dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (eluent: 25% MeOH in EtOAc to 50% MeOH in EtOAc) to yield the desired compound 348 as a yellow powder (21 mg, 59% yield).
MS (m / z) = 51 1.4 (M + H).
Step 3j N - ((2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-blpyridin-2-yl) -1-methyl-1 H-imidazol-5-yl) methyl) -N- (2-methoxyethyl) methanesulfonamido (349) To a suspension of the amine 348 (61 mg, 0.119 mmol) in DCM (5 mL) was added methanesulfonyl chloride (20.53 mg, 1.5 eq., 0.179 mmol) and Pr2NEt (46.3 mg, 3 eq., 0.358 mmol). ) and the reaction mixture is stirred at room temperature for 3 hours. The mixture is diluted with EtOAc then washed with saturated NH 4 Cl solution, saturated NaHCO 3 solution and brine. The organic phase is collected, dried over Na 2 SO 4, filtered and concentrated. The residue is purified by column chromatography (eluent to 25% MeOH in EtOAc) to yield the desired compound 349 as a pale yellow solid (34 mg, 48%). 1 H NMR (d 6 DMSO) 8.27 (s, 1 H), 8.10 (d, J = 5.48 Hz, 1 H), 7.53 (s, 1 H), 7.25 (m, 1 H), 6.95 (t, J = 9.0 Hz, 1 H), 6.76 (m, 1 H), 6.71 (s, 1 H), 6.24 (d, J = 5.48 Hz, 1 H), 6.14 (s, 1 H), 4.06 (s, 2H), 3.49 (s, 3H), 2.72 (s, 3H), 2.63 (s, 3H), 2.12 (m, 3H), 0.23 (m, 2H), 0.00 (s, 2H).
SCHEME 27 353: Example 216 Step 1: (2- (7- (4- (3- (2,4-difluorophenyl) ureido) -2-fluorophenoxy) thieno [3,2-blpyridin-2-yl) -1-methyl-1 H-imidazole -5-l) tere-butyl methyl (2-methoxyethylcarbamate (350) To a solution of aniline 46 (500 mg, 0.948 mmol) in DCM (0 mL) is added 2,4-difluoro-1-isocyanatobenzene (441 mg, 3 eq., 2.84 mmol) and the reaction mixture is stirred at room temperature. environment for 24 hours. The mixture is concentrated and purified via column chromatography (eluent 10% MeOH in EtOAc) to yield 350 (600 mg, 93%) as a white solid.
MS (m / z) = 683.7 (M + H) Step 2: 1 - (2,4-difluoropheni -3- (3-fluoro-4- (2- (5- (f2-methoxyethylamino) methyl) -1-methyl-H-imidazol-2-yl) thieno [3,2 -b1pi iloxy) phenyl) urea (351) To a solution of 350 (600 mg, 0.879 mmol) in DCM (15 mL) is added HCl in dioxane (2 mL, 7.17 eq., 8 mmol, 4M in dioxane) and the reaction mixture is stirred at room temperature for 3 hours. hours. The mixture is diluted with water and solid NaHCO3 is added. The reaction mixture is extracted with EtOAc then the organic phase is collected, dried over Na2SO4, filtered and concentrated. Trituration of the residue with EtOAc yields the desired compound 351 as an off-white solid (314 mg, 61% yield). 1 H NMR (d 6 -DMSO): 10.90 (s, 1 H), 8.89 (s, 1 H), 8.50 (d, J = 5.48 Hz, 1 H), 7.98 (m, 1 H), 7.95 (s, 1 H), 7.72 (m, 1 H), 7.41 (m, 1 H), 7.28 -7.20 (m, 3H), 7.04 (m, 1 H), 6.68 (d, J = 5.28 Hz, 1 H), 4.28 (s, 2H), 3.92 (s, 3H), 3.61 (m, 2H), 3.27 (s, 3H), 3.13 (m, 2H).
Step 3: 1 - (((2- (7- (4- (3- (2,4-difluorophenyl) ureido) -2-fluorophenoxy) thieno [3,2-blpyridin-2-yl) -1-methyl-1 H (S-Midazol-5-yl) methyl) (2-methoxyethyl) amino) -3-methyl-1-oxobutan-2-ylcarbamate of (S) -tert-butyl (352) To a solution of compound 351 (280 mg, 0.481 mmol) in DMF (10 mL) is added (S) -2- (tert-butoxycarbonylamino) -3-methylbutanoic acid (209 mg, 2 eq., 0.961 mmol), iPr2NEt (0.252 mL, 3 eq., 1442 mmol) and HATU (365 mg, 2 eq., 0.961 mmol) and the reaction mixture is stirred all night. The reaction mixture is diluted with EtOAc and washed with water, saturated solution of NAHCO3 then brine. The organic phase is collected, dried over Na 2 SO 4, filtered and then concentrated. Purification of the residue by column chromatography (eluent 20% MeOH in EtOAc) affords the desired compound 352 as an off-white solid (200 mg, 53% yield).
MS (m / z) = 782.7 (M + H).
Step 4: (S) -2-amino-N - ((2- (7- (4- (3- (2,4-difluorophenyl) ureido) -2-fluorophenoxy) thieno [3,2-blpyridin-2- il) -1-methyl-1 H-imidazol-5-yl) methyl) -N- (2-methoxyethi-3-methylbutanamide (353) To a suspension of compound 352 (200 mg, 0.256 mmol) in DCM (10 mL) is added HCI in dioxane (0.7 mL, 10.95 eq., 2.80 mmol, 4M in dioxane) and the reaction mixture is stirred at room temperature for 3 hours. The mixture is diluted with water and NaHCO3 is added. The reaction mixture is extracted with EtOAc then the organic phase is collected, dried over Na2SO4, filtered and concentrated. Purify it from the residue by column chromatography (eluent 30% MeOH in EtOAc) to yield the desired compound 353 as a pale yellow powder (155 mg, 89% yield). 1 H NMR (Ó 6 -DMSO) 9.36 (s, 1 H), 8.60 (s, 1 H), 8.49 (m, 1 H), 8.01 (m, 1 H), 7.87 (s, 1 H), 7.71 (m , 1 H), 7.41 (t, J = 8.99 Hz, 1 H), 7.31 (m, 1 H), 7.20 (m, 1 H), 7.02 (m, 1 H), 6.98 (s, 1 H), 6.65 (d, J = 5.09 Hz, 1 H), 4.83 (d, J = 15.65 Hz, 1H), 4.48 (d, J = 15.65 Hz, 1H), 3.81 (s, 1H), 3.80 (s, 3.40 ( m, 1H), 3.39-3.295 (m, 6H), 1.71 (m, 2H), 0.81 (m, 6H).
SCHEME 28 EXAMPLE 217 N1 - (3-fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) -1-methyl-1 H-imidazol-2-yl) thieno [3,2-b1pyridin-7-yloxy) phenyl ) -N3- (2-fluorophenyl) malonamide (355) Step 1j (2- (7- (2-fluoro-4- (3- (2-fluorophenylamino) -3-oxopropanamido) phenoxy) thieno [3,2-bipyridin-2-yl) -1-methyl -1 H-imidazol-5-yl) methyl (2-methoxyethyl) carbamate (354) To the solution of aniline 46 (300 mg, 0.569 mmol), acid 2 (224 mg, 1137 mmol), and DIPEA (0.397 mL, 2.274 mmol) in DMF (15 mL) is added HATU (540 mg, 1422 mmol). The reaction mixture is stirred for 16 hours at room temperature, then divided between ethyl acetate and water; the organic layer is collected, washed with water, 1 M NaOH, and brine, dried (Na2SO4) then filtered and concentrated. The residue is purified by Biotage (eluent 1 -30% MeOH / EA, silicone column 12 g) to give 354 (230 mg, 0.325 mmol, 57.2% yield) as a beige solid.
TLC: Rf = 0.35 (eluent 10% MeOH / EtOAc).
Step 2: N1 - (3-fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) -1-methyl-1 H-imidazol-2-yl) thieno [3,2-blpyridin-7-] iloxy) phenyl) -N3- (2-fluorophenyl) malonamide (355) To a solution of 354 (230 mg, 0.325 mmol) in DCM (3 mL) is added TFA (0.5 mL). The reaction mixture is stirred at room temperature the whole night afterwards he concentrates. The residue is partitioned between EtOAc and saturated NaHCO 3 solution. The organic layer is collected, dried and concentrated. The residue is purified via Biotage (0-50% MeOH / EA, 10 g SNAP column) to yield the reddish residue which is further purified by column chromatography (eluent MeOH / EA, 20-25%) to give a solid yellow which is triturated with ether to yield the title compound 355 (80 mg, 0.132 mmol, 40.5% yield) as an off-white solid.
HRMN (dmso) d (ppm) 1 H: 10.53 (s, 1 H), 10.01 (s, 1 H), 8.47 (d, 1 H, J = 5.5 Hz), 7.95 (m, 1 H), 7.85- 7.81 (m, 2H), 7.46 (t, 1 H, J = 8.8Hz), 7.39 (d, 1 H, J = 10.9Hz), 7.15-7.09 (m, 2H), 6.91 (s, 1 H), 6.65 (d, 1 H, J = 5.5Hz), 3! 81 (s, 3H), 3.72 (s, 2H), 3.58 (s, 2H), 3.35 (t, 2H, J = 5.6Hz), 3.20 ( s, 3H), 2.64 (t, 2H, J = 5.6Hz).
MS: 607.2 (MH) +.
EXAMPLE 218 2-fluoro-N- (3-fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) -1-methyl-1H-imidazol-2-yl) thienof3,2-b1pyridin-7-yloxy) phenyl) benzamide (357) Step 1 (2- (7- (2-Fluoro-4- (2-fluorobenzamido) phenoxy) thieno [3,2-blpyridin-2-yl) -1-methyl-1 H-imidazol-5-yl) methyl) Tere-butyl (2-methoxyethyl) carbamate (356) To a solution of aniline 46 (300 mg, 0.569 mmol) in DCM 810 ml) at 0 ° C is added DIPEA (0.199 ml, 1137 mmol) and 2-fluorobenzoyl chloride (135 mg, 0.853 mmol) and the suspension is stirred overnight at room temperature. The reaction mixture is concentrated and the residue is partitioned between EtOAc and water. The organic layer is collected, dried and concentrated. The residue is purified using Biotage (eluent EtOAc, HR column of silicone 25 g) to provide the title compound 356 (400 mg, 0.616 mmol, quantitative yield) as a white solid.
MS: 650 (MH) +.
Step 2: 2-Fluoro-N- (3-fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) -1-methyl-1 H-imidazol-2-yl) thieno [3,2- b1pyridin-7-yloxy) phenyl) benzamide (357) To a solution of 356 (400 mg, 0.616 mmol) and TFA (0.047 mL, 0.616 mmol) in DCM (15 mL) is added overnight at room temperature then concentrated. The residue is partitioned between EtOAc and saturated NaHCO 3 solution. The product is found in both layers. The layers are combined and concentrated. The residue is extracted with MeOH and inorganic solid is filtered. The filtrate is concentrated and the residue is purified using Btotage (eluent MeOH / EtOAc, 10-50%, silicone column of 25 g) to provide a solid which is triturated with a mixture of EtOAc / ether to produce 358 (40 mg, 0.073 mmol, 1 1.82% yield) as a white solid.
HRMN: (dmso) d (ppm) 1 H: 10.77 (s, 1 H), 8.51 (d, 1 H, J = 5.5Hz), 7.94-7.91 (m, 2H), 7.68-7.63 (m, 1 H ), 7.60-7.56 (m, 2H), 7.49 (t, 1 H), J = 8.8Hz), 7.36-7.30 (m, 2H), 7.15 (s, 1 H), 6.70 (d, 1 H, J = 5.5Hz), 4.13 (s, 2H), 3.89 (s, 3H), 3.51 (t, 2H, J = 5.3Hz), 3.26 (s, 3H), 3.01 (m, 2H).
MS: 550 (MH) + SCHEME 29 EXAMPLE 219 1-cyclopropyl-3- (3-fluoro ^ - (2- (5- (morpholinomethyl) pyridin-2-yl) thieno [3,2-blpyridin-7-yloxy) phenyl) urea (360) Step 1: 4 - ((6- (7- (2-fluoro-4-nitro-phenoxy) -thienor-3,2-blp-iridin-2-yl) pyridin-3-yl) methyl) morpholine (358) To a suspension of carbaldehyde 321 (0.5 g, 1.265 mmol) in DCM (12.65 ml) is added morpholine (0.220 ml, 2.53 mmol) and acetic acid (0.145 ml, 2.53 mmol) and the mixture is stirred for 1 hour at room temperature. before triacetoxy sodium borohydride (0.804 g, 3.79 mmol) is added. The agitation continues throughout the night. The mixture is then partitioned between DCM and 1 N NaOH. The phases are separated, the organic layer is collected, dried over sodium sulfate and concentrated. The residue is purified via Biotage (linear gradient 0-20%, MeOH / EtOAc; SNAP column 10g) to yield the title compound 358 (341 mg, 0.731 mmol, 57.8% yield) as a beige solid.
MS: 467 (MH) + Step 2: 3-Fluoro-4- (2- (5- (morpholinomethyl) pyridin-2-yl) thieno [3,2-blpyridin-7-yloxy) aniline (359) A mixture of nitro compound 358 (432 mg, 0.926 mmol), iron powder (440 mg, 7.87 mmol), and ammonium chloride (42.6 mg, 0.796 mmol) in a mixture of water (3.00 ml) and ethanol (6 ml) ) is heated at 80 ° C for 30 minutes. The reaction mixture is then filtered while heating through a pad of Celite. The filtrate is concentrated and the residue is purified using Biotage (eluent: 0-20% EtOAc / MeOH, SNAP column 10 g) to yield amine 359 (136 mg, 0.312 mmol, 33.6% yield) as a white solid.
MS: 437 (MH) +.
Step 3: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- (morpholinomethyl) pyridin-2-yl) thienof3,2-blpyridin-7-yloxy) phenyl) urea (360 ) The solution of aniline 359 (136 mg, 0.312 mmol) and DIPEA (0.218 mL, 1.246 mmol) in THF (6 mL) is cooled to 0 ° C, and then triphosgene (46.2 mg, 0.156 mmol) is added and the reaction mixture is stirred for 1 hour at 0 ° C followed by the addition of cyclopropylamine (89 mg, 1558 mmol).
The reaction mixture is stirred at room temperature for additional 3 hours then concentrated, partitioned between water and ethyl acetate. A sticky solid is formed which is isolated by suction filtration, rinsed with water and ethyl acetate, and dried in vacuo. This material is then purified using Gilson (eluent 20-95% MeOH / H 2 O, 1 h) to give the title compound 360 (30 mg, 0.058 mmol, 18.53% yield) as a white solid. 1H: HRMN 9.16 (s, br, 1 H), 8.16 (d, 1 H, J = 1.6 Hz), 8.1 1 (d, 1 H, J = 5.4 Hz), 7.91 (s, 1 H), 7.83 ( d, 1 H, J = 8.2Hz), 7.46 (dd, 1 H, J1 = 2.1 Hz, J2 = 8.2Hz), 7.34 (dd, 1 H, J 1 = 2.6Hz, J2 = 13.9Hz), 6.97- 7.45 (m, 2H), 6.84-6.81 (m, 1 H), 6.23 (d, 1 H, J = 4.7Hz), 3.18 (t, 4H), 3.14 (s, 2H), 2.15-2.12 (m, 1 H), 1.98 (m, 4H), 0.23-0.19 (m, 2H), 0.02-0.005 (m, 2H).
MS: 520.4 (MH) +.
SCHEME 30 368: Example 220 EXAMPLE 220 1 - . 1 - (4- (2- (4-5,8,11-trioxa-2-azadodecylphenyl) thienor3,2-blpyridin-7-yloxy) -3-fluorophenyl) -3- (5-methylisoxazole-3-) il) urea (368) Step 1: 4- (7- (2-fluoro-4-nitrophenoxy) thienof3,2-b1pyridin-2-D-benzaldehyde (362) Yodothienopyridine 361 (US 2006/0287343) (2.10 g, 5.05 mmol), 4-formylphenylboronic acid (1.51 g, 10.1 mmol) is dissolved, and tetrakis (triphenylphosphine) palladium (0.29 g, 0.25 mmol) is dissolved in dry dioxane (80 my). Cesium fluoride (0.92 g, 6.1 mmol) and sodium bicarbonate (2.12 g, 25.2 mmol) are dissolved in water (5 ml each) and added to the reaction mixture, which is degassed with a stream of N2, then heat to reflux for 3 hours, cool and concentrate. The residue is partitioned between ethyl acetate and water, resulting in a thin precipitate. This is isolated by suction filtration and rinsed with water and ethyl acetate to yield 362 (1.92 g, 96%).
LREM (M + H): 395.2 Step 2: N, N- (4- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b1pyridin-2-yl) benzyl) -2- (2- (2-methoxyethoxy) ethoxy) ethanamine (364) A suspension of 362 (0.90 g, 2.3 mmol), 363 amine (0.93 g, 5.7 mmol) [363 amine has been synthesized according to the procedures used for the synthesis of amines (322 (scheme 18) and 326 (scheme 20) ) and acetic acid (0.26 ml, 4.6 mmol) in dichloromethane (50 ml) is stirred for 1 hour at room temperature. Then sodium triacetoxyborohydride (1.45 g, 6.85 mmol) is added and the mixture is stirred at room temperature for 16 hours. An additional amount of sodium triacetoxyborohydride (1.5 g) is then added, and the stirring is continued for 2 hours. The reaction mixture is partitioned between dichloromethane and 1 N HCl. The organic phase is discarded. The aqueous phase is basified (pH = 13) with 3M NaOH, and extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulfate, filtered and concentrated to yield 364 (0.72 g, 58%) as a yellow solid.
LREM (M + H): 542.4.
Stage 3: 4- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-blpyridin-2-yl] benzyl (tere-butyl 2- (2- (2-methoxyethoxy) ethoxy) ethyl) carbamate (365) To a solution of 364 (0.72 g, 1.3 mmol) in dichloromethane (100 ml) at room temperature is added DMAP (0.041 g, 0.33 mmol) and Boc20 (0.58 g, 2.7 mmol). The reaction mixture is stirred at room temperature for 2 hours then the mixture is washed consecutively with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (eluent EtOAc then 1% MeOH in EtOAc) to yield compound 365 (0.51 g, 60% yield).
LREM (M + H): 642.5 Stage 4: 4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-blpyridin-2-yl) benzyl (tere-butyl 2- (2- (2-methoxyethoxy) ethoxy) carbamate) (366 ) To a solution of 365 (0.49 g, 0.76 mmol) in MeOH (100 mL) is added iron powder (0.43 g, 7.6 mmol) and ammonium chloride (0.12 g, 2.3 mmol) in water (5 mL). The resulting mixture is refluxed for 4 hours, then cooled, filtered through celite pad and concentrated. The residue is divided between dichloromethane and water; the organic phase is collected, washed with brine, dried over magnesium sulfate Anhydrous, filtered and concentrated. The residue is purified by chromatography on silica gel (eluent 2% MeOH in EtOAc) to provide 366 (0.41 g, 88% yield).
LREM (M + H). 612.6 Step 5j 4- (7- (2-fluoro-4- (3- (5-methylisoxazol-3-yl) ureido) phenoxy) thienof3,2-blpyridin-2-yl) benzyl (2- (2- (2- tert-butyl methoxyethoxy) ethoxy) ethyl) carbamate (367) To a solution of 366 (0.15 g, 0.25 mmol) and DIPEA (0.1 ml, 0.080 g, 0.61 mmol) in tetrahydrofuran (50 ml) at 0 ° C is added triphosgene (0.029 g, 0.098 mmol) and the resulting solution stir for 1 hour at 0 ° C. 3-Amino-5-methylisoxazole (0.025 g, 0.25 mmol) is added and the mixture is heated to room temperature and stirred for 3 hours, then quenched with 1 ml of water and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and water; The organic phase is collected, washed with brine, dried over MgSO 4, filtered and concentrated. The product is purified by chromatography on silica gel (eluent: 2% MeOH in EtOAc) to give 367 (0.074 g, 4% yield).
Step 7: 1- (4- (2- (4, 5,8,1 1-trioxa-2-azadodecylphenyl) thienor 3,2-blpyridin-7-yloxy) -3-fluorophenyl) -3- (5-methylisoxazole- 3-yl) urea (368) To a solution of 367 (0.074 g, 0.10 mmol) in dichloromethane (50 mL) is added trifluoroacetic acid (1.0 mL). The reaction mixture is stirred for 3 hours at room temperature then it is concentrated and the residue is partitioned between dichloromethane and saturated NaHCO3. The organic phase is collected, washed with brine, dried over MgSO 4, filtered and concentrated. The residue is purified by Gilson reverse phase HPLC (35-75% MeOH / H20, Aquasil Cie, 30 min) and lyophilized. The purified product (which contains some form of HPLC formic acid) is divided between dichloromethane and 1 M NaOH). The organic phase is collected, dried (MgSO 4), filtered and concentrated to give compound 368 (0.033 g, 0.052 mmol, 52% yield). 1 H: 9.71 (s, 1 H); 9.31 (s, 1 H); 8.48 (d, J = 5.5, 1 H); 8.01 (s, 1 H); 7. 82-7.79 (m, 2H); 7.73 (dd, J = 13.1, 2.5, 1 H) 7.46-7.41 (m, 3H) 7.28-7.26 (m, 1 H); 6.60 (d, J = 5.5, 1 H); 6.54 (d, J = 0.8, 1 H); 3.75 (s, 2H); 3.51 -3.45 (m, 8H); 3.41 -3.35 (m, 2H); 3.20 (s, 3H); 2.63 (t, J = 5.7, 2H); 2.35 (d, J = 0.6, 3H).
LREM (M + H): 636.5 SCHEME 31 EXAMPLE 221 N- (4- (7- (2-fluoro-4- (3- (5-methylisoxazol-3-yl) ureido) phenoxy) thienor3,2-blpyridin-2-yl) benzyl) -N- (2- ( 2- (2-methoxyethoxy) ethoxy) ethyl) acetamide (371) Step 1: N- (4- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-blpyridin-2-yl] benzyl) -N- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) acetamide (369) To a solution of 364 (0.50 g, 0.92 mmol) in dry tetrahydrofuran (50 mL) is added acetic anhydride (1.0 mL, 11 mmol). The reaction mixture is stirred for 24 hours at room temperature then concentrated. The residue is partitioned between ethyl acetate and water; The organic phase is collected, washed with NaHCO3, brine, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography on silica gel (eluent EtOAc) to give 369 (0.36 g, 67% yield).
LREM (M + H): 584.4 Step 2 N- (4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b1-pyridin-2-yl] benzyl) -N- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) acetamide (370) To a solution of 369 (0.36 g, 0.62 mmol) in MeOH (100 mL) is added iron powder (0.68 g, 12 mmol) and ammonium chloride (0.13 g, 2.5 mmol) in water (5 mL). The resulting mixture is refluxed for 4 hours, then cooled through celite and concentrated. The residue is divided between dichloromethane and water; The organic phase is collected, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The product is purified by chromatography on silica gel (eluent 2% MeOH in EtOAc) to provide 370 (0.35 g, 100% yield).
LREM (M + H): 554.4 Step 3 N- (4- (7- (2-Fluoro-4- (3- (5-methylisoxazol-3-yl) ureido) phenoxy) thienor3,2-b] pyridin-2-yl) benzyl) -N- (2- (2- (2-methoxyethoxy) ethoxy) etl) acetamide (371) To a solution of 370 (0.14 g, 0.25 mmol) and DIPEA (0.11 mL, 0.080 g, 0.61 mmol) in tetrahydrofuran (50 mL) at 0 ° C is added triphosgene (0.030 g, 0.10 mmol) and the resulting solution is stirred for 0.5 hours at 0 ° C. 3-Amino-5-methylisoxazole (0.074 g, 0.76 mmol) is added and the mixture is warmed to room temperature and stirred for 3 hours, then quenched with 1 ml of water and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and water, the organic phase is collected, washed with brine, dried over MgSO 4, filtered and concentrated. The product is purified by chromatography on silica gel (10% MeOH in EtOAc), followed by Gilson reverse phase HPLC (35-65% acetonitrile / H20, Aquasil Cie, 30 min) and lyophilized. The residue (which contains some formic acid of HPLC) is divided between dichloromethane and 1 M NaOH. The organic phase is dried (MgSO4), filtered and concentrated to provide 371 (65 mg, 38% yield) as a mixture. 2: 1 of rers by 1 H NMR. 1 H NMR (DMSO-d 6) d (ppm) 1 H: 9.64 (s, 1 H); 9.19 (s, 1 H); 8.50-8.48 (m, 1 H); 8.04 (s, 0.4H); 8.01 (s, 0.6H); 7.89 (d, J = 8.2, 0.4H); 7.82 (d, J = 8.2, 0.6H); 7.72 (dd, J = 12.9, 2.5, 1 H) 7.45 (t, J = 9.2, 1 H); 7.33 (d, J = 8.4, 2H); 7.27-7.24 (m, 1 H); 6.61-6.59 (m, 1 H); 6.54 (d, J = 0.8, 1 H); 4.68 (s, 0.4H); 4.59 (s, 0.6H); 3.52-3.38 (m, 12H); 3.21 (s, 1.8H); 3.20 (s, 1.2H); 2.35 (d, J = 0.4, 3H); 2.12 (s, 1 .8H); 2.00 (1.2 H).
LREM (M + H): 678.8.
SCHEME 32 EXAMPLE 222 3-Fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b1pyridin-7-yloxy) phenylcarbamate of 2,2,2-trifluoroethyl (373) Step 1: 4- (2- (5 - ((tert-Butoxycarbonyl (2-methoxyethyl) amino) methyl) pyridin-2-yl) thieno [3,2-blpyridin-7-yloxy) -3-fluoropheni-methylcarbamate , 2,2-trifluoroethyl (372) Diphosgene (0.017 ml, 0.143 mmol) is added to a solution of aniline 126 (0.15 g, 0.286 mmol) in THF (2.86 ml) and the reaction mixture is stirred vigorously for 2 hours. To the reaction mixture is added 2,2,2-trifluoroethanol (0.042 mL, 0.572 mmol) and a solution of DIPEA (0.100 mL, 0.572 mmol) in THF (2.86 mL). The reaction mixture is stirred vigorously overnight, diluted with DCM, washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is purified by flash chromatography (Biotage, 10 Snap column, gradient: 3% of 10 CV, 3% to 5% of 2 CV, and 5% of 10 CV of MeOH in DCM) yielding 372 (0.1097 g, 0.169 mmol , 59.0% yield) as a light brown solid, m / z: 651.4 (M + H) +.
Step 2j 3-Fluoro-4- (2- (5 - ((2-methoxyethylamino) methoxy-ethylamino) methyl) pyridin-2-yl) thieno [3,2-blpyridin-7-yloxy) phenylcarbamate 2.2, 2-trifluoroethyl (373) To a suspension of 372 (0.1097 g, 0.169 mmol) in DCM (1.0 mL) is added TFA (1.0 mL, 12.98 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in DCM, washed with 1 N NaH solution, dried over anhydrous sodium sulfate and concentrated under pressure to yield 373 (0.0543 g, 0.097 mmol, 57.3% of performance) as a white solid. 1 H NMR (DMSO-D 6, 400 MHz) 10.55 (s, 1 H), 8.57 (s, 1 H), 8.52 (d, J = 5.62 Hz, 1 H), 8.32 (s, 1 H), 8.23 ( d, J = 8.1 Hz, 1 H), 7.90 (d, J = 8.10 Hz, 1 H), 7.63 (d, J = 9 Hz, 1 H), 7.52 (d, J = 13.5 Hz, 1 H), 7.39 (t, J = 9.0Hz, 1H), 6.66 (d, J = 6.7Hz, 1H), 4.85 (q, J = 9.0Hz, 2H), 3.79 (s, 2H), 3.41 (t, J = 5.5 Hz, 2H), 3.24 (s, 3H), 2.66 (t, J = 5.5Hz, 2H). m / z: (M + H) + 551.4 SCHEME 33 TO 376: Example 223 EXAMPLE 223 N- (3-Fluoro-4- (2- (5 - ((2-methoxyethylamino) methyl) pyridin-2-yl) thienor3,2- b] pyridin-7-yloxy) phenylcarbamoyl) cyclopropanesulfonamide (376) Step 1: Ethyl cyclopropylsulfonylcarbamate (374) To a solution of cyclopropanesulfonamide (Li, J et al., Synlett 2006, 5, 725-728) (800 mg, 6.60 mmol) in acetone (25 ml) is added potassium carbonate ( 2738 g, 3 eq 19.81 mmol) and ethyl chloroformate (1.075 g, 1.5 eq, 9.90 mmol) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is poured into water and made acidic (pH 1) with concentrated HCl then extracted with EtOAc. The extract is collected, dried over Na 2 SO 4, filtered and concentrated. Purification of the residue by column chromatography (eluent 30% EtOAc in hexanes) yields 374 as a colorless oil (800 mg, 63%). 1 H NMR (DMSO, d.6) 1 1 .47 (s, 1 H), 4.10 (q, J = 10.27 Hz, 2H), 2.90 (m, 1 H), 1 .19 (t, J = 7.24 Hz , 3H), 1.039 (m, 4H).
Step 2j (6- (7- (4- (3- (cyclopropylsulfonyl) ureido) -2-fluorophenoxy) t'enof3,2-blpyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) tere-butyl carbamate (375) To a solution of the amine 126 (500 mg, 0.953 mmol) in DME (4 ml) is added carbamate 374 (460 mg, 2.5 eq 2.383 mmol) and the reaction mixture is heated at 120 ° C for 1 day. The mixture is cooled to room temperature, diluted with EtOAc and water and the organic phase is collected, dried over Na 2 SO 4, filtered and concentrated. Purification of the residue by column chromatography (eluent of EtOAc to 50% acetone in EtOAc) yields 375 as a brown oil (130 mg, 55%).
MS (miz) = 672.5 (M + H) Step 3: N- (3-Fluoro-4- (2- (5- (82-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b] pyridin-7-yloxy) phenylcarbamoyl) cyclopropanesulfonamido (376) To a solution of 375 (140 mg0.208 mmol) in DCM (5 mL) is added HCI in dioxane (0.5 mL, 2 mmol, 9.6 eq 4M in dioxane) and the reaction mixture is stirred for 4 hours. The mixture is diluted with EtOAc, made basic with NaHCO 3 solution and extracted with EtOAc / acetone. The organic phase is collected and discarded. The aqueous phase is concentrated and the residue is suspended in a mixture of DCM and acetone. The solution phase is collected, dried over Na2SO4, filtered and concentrated to yield 376 as a beige solid after further trituration with Et20 (yield 8 mg 7%). 1 H NMR (DMSO-d 6): 8.67 (s, 1 H), 8.56 (s, 1 H), 8.47 (d, J = 5.28, 1 H), 8.27 (s, 1 H), 8.19 (d, J = 8.02 Hz, 1 H), 7.85 (m, 2H), 7.80 (s, 1 H), 7.22 (m, 2H), 6.59 (d, J = 5.28 Hz, 1 H), 3.76 (s, 2H), 3.40 (m, 2H), 3.20 (s, 3H), 2.76 (m, 1 H), 2.60 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2H).
LREM (ESI): (calculated) 571.64 (found) 572.58 (MH) +.
Additional compounds according to the present invention include those in Table 2.
TABLE 2 ] H NMR (DMSO-d6) d (ppm): 9. 55 (s, 1H), 8.92 (s, 1H), 8.48 (m, 1H), 8.0) m, 1H), 7.85 (s, 1H), 7.72 (m, 1H), 7.42 (t, J = 8.9 Hz) , 1H), 7.30 - 7.20 (m, 2H), 6.91 (s, 1H), 227 N 6.81 (m, 1H), 6.64 (d, J = 5.48 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 1- (2,5-difluorophenyl) -3- (3-fluoro-4- (2- (5-2H), 3.36 (t, J = 5.67 hz, 2H), ((2-methoxyethylamino) methyl) -1 -methyl-1 H- 3.20 (s, 3H), 2.64 (t, J = 5.67 imidazol-2-yl) thieno [3,2-b] pyridine-7 Hz, 2H). iloxy) phenyl) urea LREM (ESI): (calc.) 582.60 (encont.) 583.5 (MH) + NMR (DMSO-d6) d (ppm): 8.96 (s, 1H), 8.59 (s, 1H), 8.47 (d, 1H, J = 5.5Hz), 7.85 (s, 1 0 OMe 1H), 7.70 (dd, 1H, J1 = 2.3Hz, J2 = 13.3Hz), 7.38 (t, 1H, J = 9.0Hz), 7.33-7.31 (m, 2H), N N 7. 21-7.18 (171, 1H), 6.91 (s, 1H), 228 6. 85-6.83 (m, 2H), 6.63 (d, 1H, J = 5.3Hz), 3.87 (s, 3H), 3.72 (s, 1- (3-fluoro-4- (2- (5 - ((2- 2H), 3.67 (s, 3H), 3.36 (t, 2H, methoxyethylamino) methyl) -1-methyl-1 H- J = 5.6 Hz), 3.19 (s, 3H), 2.65 (t, imidazol-2-yl) thieno [3,2-b] pyridin-7-2H, J = 5.5Hz). iloxy) phenyl) -3- (4-methoxyphenyl) urea LREM (ESI): (calc.) 576.2 (encont.) 577.5 (MH) + NMR (DMSO-d6) d (ppm): 9.15 (s, 1H), 9.02 (s, 1H), 8.48 (d, J = 5.28 Hz, 1H), 7.86 (s, 1H), 7.81 (m, 1H) , 7.70 (m, 1H), 7.41 (t, J = 8.99 Hz, 1H), 7.31 (m, 1H), 7.24 (m, 3H), 229 H 1 / > _ J 7.14 (m, 1H), 6.94 (s, 1H), 6. 64 (d, J = 5.28 Hz, 1H), 3.87 1- (3-bromophenyl) -3- (3-fluoro-4- (2- (5 - ((2- (s, 3H), 3.77 (s, 2H), 3.375 (t, methoxyethylamino) methyl) -1 -methyl-1 H- J = 5.48 hz, 2H), 3.20 (s, 3H), imidazol-2-yl) thieno [3,2-b] pyridin-7- 2.69 (t, J = 5.48 Hz, 2H) iloxy) phenyl) urea LREM (ESI): (calc.) 625.51 (encont.) 625.4 / 627.4 (MH) + Additional compounds according to the present invention include those in Table 3 TABLE 3 Additional compounds according to the present invention include those in Table 4.
TABLE 4 Additional compounds according to the present invention include those in Table 5.
TABLE 5 Additional compounds according to the present invention include those in Table 5a.
TABLE 5A Pharmaceutical compositions In some embodiments, the invention provides pharmaceutical compositions comprising a compound according to the invention and a pharmaceutically acceptable carrier, excipient or diluent. Compositions of the invention can be formulated by any method well known in the art and can be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical intranasal, intratracheal, or intrarectal. In some embodiments, the compositions of the invention are administered intravenously in a hospital setting. In some modalities, the administration can be by the oral route.
The characteristics of the carrier, excipient or diluent will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as cell, cell culture, tissue or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient (s). . In this manner, the compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, stabilizers, solubilizers, or other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, for example, Remington's Pharmaceuticals Sciences, 18th edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa, 1990.
The active compound is included in the pharmaceutically acceptable carrier, excipient or diluent in an amount sufficient to deliver a therapeutically effective amount to a patient without causing serious toxic effects in the treated patient. The effective dosage range of a pharmaceutically acceptable derivative can be calculated based on the weight of the source compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those of skill in the art.
Inhibition of VEGF receptor signaling In some embodiments, the invention provides a method for inhibiting VEGF receptor signaling in a cell, comprising contacting a cell in which the inhibition of VEGF receptor signaling is desired with an inhibitor of VEGF receptor signaling according to the invention. with the invention Because the compounds of the invention inhibit VEGF receptor signaling, these are useful research tools for in vitro study of the function of VEGF receptor signaling in biological procedures.
In some embodiments, the inhibition of VEGF receptor signaling causes an inhibition of cell proliferation of contacted cells.
EXAMPLE OF ASSAY Inhibition of VEGF activity The following protocol is used to test the compounds of the invention.
EXAMPLE OF ASSAY 1 Assay of the tyrosine kinase receptor in vitro (VEGF KDR receptor) This test measures the ability of the compounds to inhibit the enzymatic activity of the enzymatic activity of the recombinant human VEGF receptor.
A 1.6-kb cDNA corresponding to the catalytic domain of VEGFR2 (KDR) (Genbank accession number AF035121 amino acid 806 to 1 356) is cloned into the Pst 1 site of the Gateway vector pDEST20 (Invitrogen) for the production of a GST-version. labeled of this enzyme. This construct is used to generate recombinant baculovirus using the Bac-toBac ™ system according to the manufacturer's instructions (Invitrogen).
The GST-VEGFR2806-1356 protein is expressed in Sf9 cells (Spodoptera frugiperda) in infection with recombinant baculovirus construct. Briefly, sf9 cells grow in suspension and are maintained in serum-free medium (sf900 II supplemented with gentamicin) at a cell density of approximately 2 X 10 6 cells / ml are infected with viruses mentioned above at a multiplicity of infection (MOI) of 0.1. for 72 hours at 27 ° C with agitation at 120 rpm on a rotary shaker. Infected cells are collected by centrifugation at 398 g for 15 minutes. Cell pellets are frozen at -80 ° C until the purification is performed.
All the steps described in cell extraction and purification are carried out at 4 ° C. Sf9 cell pellets infected with GST-baculovirus recombinate VEGFR2806-1356 are thawed and gently resuspended in buffer pH A (PBS pH 7.3 supplemented with 1 ng / ml pepstatin, 2 g / ml aprotinin and leupeptin, 50 μg / ml) of PMSF, 50 μ9 / λ of TLCK and 10 μ of E64 and 0.5 mM of DTT) using 3 ml of pH regulator per gram of cells. The suspension is homogenized by Dounce and 1% Triton X-100 is added to the homogenate after which it is centrifuged at 22500 g, 30 minutes, 4 ° C. The supernatant (cell extract) is used as the starting material for the purification of GST-VEGFR2806-356.
The supernatant is loaded onto a GST-agarose column (Sigma) equilibrated with PBS pH 7.3. Following four column volume washes (CV) with PBS pH 7.3 + 1% Triton X-100 and 4 CV washes with pH regulator B (50 mM Tris pH 8.0, 20% glycerol and 100 mM naCl), proteins bound are eluted in stages with 5 CV of pH buffer supplemented with 5 mM DTT and 15 mM glutathione. Fractions enriched with GST-VEGFR2806-1356 from this chromatography step is combined based on UV traces ie fractions with O.D. 280 high. Concentrations of final GST-VEGFR2806-1356 protein preparation are approximately 0.7 mg / ml with purity of approximately 70%. Purified GST-VEGFR2806-1356 protein samples are aliquoted and frozen at -80 ° C before being used in the enzyme assay.
Inhibition of VEGFR / KDR is measured in a DELFIATM assay (Perkin Elmer). The poly (Glu4, Tyr) substrate is immobilized in 96-well black high-styrofoam plates. The coated plates are washed and stored at 4 ° C. During the assay, the enzyme is pre-incubated with inhibitor and MgATP on ice in 96-well polypropylene plates for 4 minutes, and then transferred to the coated plates. The consecutive kinase reaction takes place at 30 ° C for 10-30 minutes. The concentrations of ATP in the assay are 0.6 μp? for VEGFR / KDR (2Xel Km). The enzyme concentration is 5 nM. After incubation, the kinase reactions are quenched with EDTA and the plates washed. The phosphorylated product is detected by incubation with anti-phosphotyrosine Europium-labeled MoAb. After washing the plates, MoAb binding is detected by fluorescence resolved in time in a Gemini SpectraMax reader (Molecular Devices). Compounds are evaluated over the range of concentrations of and CI150's (concentration of compounds that provide 50% inhibition of enzymatic activity) are determined. The results are shown in table 6. In the table, "a" indicates inhibitory activity at a concentration of less than 250 nanomolar; "b" indicates inhibitory activity at a concentration > 500 but < 1000 nanomolar, and "d" indicates inhibitory activity > 1000 nanomolar.
EXAMPLE OF ASSAY 2 Erk phosphorylation dependent on VEGF Cells and growth factor: HUVEC cells were purchased from Cambrex Bio Science Walkersville, Inc and are grown according to the vendor's instructions. The sequence encoding the full length of VEGF165 is cloned using Cloning Technology gateway (Invitrogen) for Sf9 baculovirus expression cells. VEGF165 is purified from conditioned medium using a NaCl elution gradient from a HiTrap heparin column (GE Healthcare Life Sciences) followed by an imidazole elution gradient from a HiTrap chelation column (GE Healthcare Life Sciences), then stored pH regulator in PBS supplemented with 0.1% BSA and sterilized filter.
Cell assays, the cells are seeded in 8000 cells / well of a 96-well plate and grown for 48 hours. The cells are then grown overnight in serum and growth factor-free medium and exposed for 1.5 hours to dilutions of compounds. Following a 15-minute incubation in the medium, VEGF 65 cells (150 ng / ml) are lysed in an ice-cooled pH buffer (50 mM HEPES, pH 7.4, 150 mM NaCl !, 1.5 mM MgCl2, 1% Triton X-100, 10% glycerol) containing 1 mM of 4- (2-aminoethyl) benzenesulfonyl fluoride hydrochloride, 100 μg sodium orthovanadate, 1 mM sodium fluoride, 10 ng / ml of leupeptin, 10 g / ml of aprotinin, 1 μg / ml of pepstatin and 50 μg / ml of Na-p-tosyl-L-lysine chloromethyl ketone hydrochloride and processed as Western blots to detect anti-phospho ERK1 / 2 (T202 / Y204) (Cell Signaling Technologies).
Western blot analysis: Single treatment well lysate samples are separated on 5-20% SDS-PAGE gels and immunoblotted using Immobilon polyvinylidene difluoride membranes (Amersham) according to the manufacturer's instructions. The spots are washed in Tris pH regulated saline with 0.1% Tween 20 detergent (TBST) and tested for antibodies against Thr202 / Tyr204-ERK (Cell signaling technologies, Chemiluminescence detection (Amersham, ECL plus) is performed in accordance with manufacturer's instructions using Store densitometer (GE Healthcare; 800 MT, 100 nM resolution) for image formation and densitometry analysis.The values on the dissolution interval are used to prepare IC50 curves using parameter adjustment model 4. These Curves are calculated using software GraFit 5.0 The results are shown in table 6. In the table, "a" indicates the inhibitory activity at a concentration of less than 250 nanomolar, "b" indicates the inhibitory activity at a concentration of > 250 but <500 nanomolar, "c" indicates the inhibitory activity at> 500 but 1000 nanomolar, and "d" indicates inhibitory activity> 1000 nanomolar.
TABLE 6 EXAMPLE OF ASSAY 2 Solid tumor disease model in vivo This test measures the compound's ability to inhibit solid tumor growth.
Tumor xenografts are established on the flank of female CD1 atimic mice (Charles River Inc.) by subcutaneous injection of 1 X106 U87, A431 or SKLMS / mouse cells. Once it is established, tumors are then passed serially. in guests of nude mice. Tumor fragments from these host animals are used in subsequent compound evaluation experiments. For nude female mice from compound evaluation experiments. For Female nude mice from compound evaluation experiments weighing approximately 20 g are implanted s.c. by surgical implantation with tumor fragments of ~ 30 mg of donor tumors. When the tumors are approximately 100 mm3 in size (-7-10 days after implantation), the animals are randomly chosen and separated into the treatment and control groups. Each group contains 6-8 tumor-bearing mice, each of which is labeled on the ear and then individually through the experiment.
Mice are weighed and tumor measurements are taken by calibrators three times weekly starting at day 1. These tumor measurements are converted to tumor volume by the well-known formula (L / W / 4) 3 4 / 3p. The experiment ends when the control tumors reach a size of approximately 1500 mm3. In this model, the change in mean tumor volume for a group treated with compound / the change in mean tumor volume of the control group (untreated or vehicle treated) x 100 (AT / AC) is subtracted from 100 to provide the percentage of inhibition of tumor growth (% TGI) for each test compound. In addition to tumor volumes, the body weight of animals is monitored twice weekly for up to 3 weeks.
EXAMPLE OF ASSAY 3 Choroidal in vivo neovascularization model (CNV) This test measures the ability of compounds to inhibit CNV progression. CNV is the leading cause of severe vision loss in patients suffering from age-related macular degeneration (AMD).
Rats Brown-Norway (Japan Clea Co., Ltd) is used in these studies.
Rats are anesthetized by intraperitoneal injection of pentobarbital, and the right pupil is dilated with 0.5% tropicamide and 0.5% phenylephrinephine hydrochloride. The right eye receives 6 laser burns between the retinal vessels using a slit lamp supply system from Green Laser Photocoagulator (Nidex Inc., Japan), and a microscope slide with Healon ™ (AMO Inc) is used as a lens. Contact. The laser energy is 100 to 200 mW for 0.1 seconds and the diameter of the spot is 100 μ. At the time of the laser beam, the production of bubbles is observed, which is an indication of rupture of the Bruch membrane that is important for the generation of CNV.
Rats are divided into groups based on their body weight using SAS software (Japan SAS Institute R8.1) after laser irradiation (Day 0). After the animals are anesthetized, and the right pupil is dilated (as mentioned above), the animal's right eye receives the compound or vehicle by injection (10 μ? / Eye) at a dose of 30 nmol / eye per day 3. The compounds are dissolved or suspended in CBS, PBS or other suitable vehicles before injection.
On day 10, the animals are anesthetized with ether, and fluorescein isocyanate (FITC) - high molecular weight dextran (SIGMA, 2 x 106 PM) is injected via a tail vein (20 mg / rat). Approximately 30 minutes after the injection of FITC-dextran, the animals are painlessly killed by ether or carbon dioxide, and the eyes are removed and fixed with 10% neutral pH buffer of 10% formalin. After around fixation, flat supports of RPE-choroid-sclera are obtained by recovering the cornea, lenses and retina of the eyeballs. The flat supports are mounted in 50% glycerol on one microscopic side, and the laser burned portion is photographed using a fluorescent microscope (Nikon Corporation, excitation filter: 465-495 nm, absorption filter: 515-555 nm). The CNV area is obtained by measuring the hyper-fluorescent area observed in the photograph using Scion image.
The average CNV area of 6 burns is used as an individual value of the CNV area, and the average CNV area of the compound treated group is compared to that of the vehicle treated group. The results with some compounds of the present invention are shown in table 7 and are indicated as% inhibition of CNV progression ("A" indicates more than equal to 60% inhibition, and "B" indicates> 40% a <60% inhibition).
TABLE 7

Claims (35)

  1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula (I): D M (I) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and their complexes, and racemic and stepmic mixtures, diastereomers and enantiomers thereof, wherein, D is selected from group consisting of an aromatic ring system, heteroaromatic, cycloalkyl or heterocyclic, each of which is optionally replaced with 1 to 5 independently selected R38; M is a optionally substituted heterocyclic fused radical; Z is -O-; Ar is a 5 to 7 member aromatic ring system, which is optionally substituted with 0 to 4 groups R2, and G is a group B-L-T, where B is -N (R13) - or -C (= S) -; L is selected from the group consisting of -C (= 0) N (R13) -, -C (= O) C0-C1alkyl-C (= O) N (R13) -, and -C (= 0) -, wherein an alkyl group of the group L mentioned above is optionally substituted, and T is selected of the group consisting of -Co.Calkyl, -C0-C5alkyl-Q, -O-C0-C5alkyl-Q, -O-Co- C5alkyl, -C (= S) -N (R13) -C0-C5alkyl-Q, -C0-C5alkyl-S (O) 2-Q, and -C (= S) -N (R13) - Co-C5alkyl, wherein each Co-Csalkyl is optionally substituted; wherein each R38 is independently selected from the group consisting of halo, C C6 optionally substituted alkyl, -C0-C6alkyl- (optionally substituted heterocycle), -C2-C6alkenyl = N-heterocycle-CrC6alkyl optionally substituted, -CH = N-heterocycle optionally substituted, - (CH ^ NR ^ CH ^ R36, -C (0) (CH2) jNR39 (CH2) nR36, - (CH2) jNR39 (CH2) ¡[O (CH2) 1] x (CH2) iR99, - (CH2) jNR39C (0) (CH2) iO (CH2) jOR3, - (CH2) jNR39 (CH2) j (CH) (NH2) (COOH), - (CH2) iNR39CH (CH3) (CH2) jR99 and - ( CH2) jNR39 (CH2) jCOOH, where each j is an integer independently ranging from 0 to 4, n is an integer that varies from 0 to 6, x is an integer ranging from 0-6, each i is independent 2 or 3, and the radicals (CH2) n-of the above groups R38 are optionally substituted with Cr C6alkyl, R36 is H or - (CH2) n30R37, where n3 is an integer ranging from 0 to 6; except that when R36 and R39 are both bound to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen; each R37 is independently selected from H, C C6 alkyl, - (CH2) nO (CH2) aO-CrC6alkyl, - (CH2) nCH (NH) (CH2) nO-Ci-C6alkyl, - (CH2) nCH (NH) ( CH2) nC1-C6alkyl, - (CH2) nO (CH2) aO-C3-C10cycloalkyl, - (CH2) nCH (NH) (CH2) nO-C3-C ^ cycloalkyl and - (CH2) nCH (NH) ( CH2) nC3-C1-cycloalkyl, where each n is an integer independently varying from 0 to 6 is already an integer ranging from 2 to 6, wherein the alkyl and cycloalkyl radicals of the above R37 groups are optionally substituted by one or more substituents selected independently; R39 is selected from the group consisting of H, C C6 alkyl, -S02-CrC6alkyl, -C (0) -CrC6 alkyl, -C (0) 0-CrC6alkyl, -C (O) -CrC6alkyl-NR3R3, -CrC6alkyl-0 -C -C6alkyl, -C (O) (CH2) o -4O (CH2) 1.40Ci-C6alkyl, -C (O) -C C6alkyl-OH, -C (0) -CF3 and -C (0) CH [CH (C C6alkyl) 2] NR3R3 and a protecting group used to protect secondary amino groups with the proviso that when R36 and R39 are both bound to the same nitrogen, then R36 and R39 are not both bound to nitrogen directly through an oxygen; R99 in each occurrence is independently -H, -NH2 or -OR3; R2 at each occurrence is independently selected from -H and halogen; each R3 is independently selected from the group consisting of -H and R4; R4 is (Ci-C6) alkyl; each R13 is independently selected from the group consisting of -H, -C (0) NR3R3 and Ci-C6 alkyl; Q is a ring system of three to ten members, optionally substituted with between zero and four of R20; and each R20 is independently selected from the group consisting of -H, halogen, trihalomethyl, -OR3, -S (O) 0.2R3, -S (O) 2NR3R3, -C (O) OR3, -C (O) NR3R3, - (CH2) o-5 (heteroaryl), CrC6alkyl, wherein n is an integer ranging from 0 to 6, and the heteroaryl and dC6 alkyl are optionally substituted. 2 - . 2 - The compound according to claim 1, further characterized in that D is an aromatic or heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R38 groups. 3. - The compound according to claim 1, further characterized because D is a heteroaromatic ring system of 5 or 6 members, each of which is replaced with 1 or 2 R38 groups selected independently 4. The compound according to claim 1, further characterized in that D is a 6-membered aromatic ring system or a 6-membered heteroaromatic ring system, each of which is substituted with 1 or 2 independently selected R38 groups. 5. The compound according to claim 1, further characterized in that D is a 6-membered aromatic ring system, substituted with 1 or 2 R38 groups selected independently. 6. - The compound according to claim 1, further characterized in that D is a heteroaromatic ring system of 6 members, replaced by 1 or 2 R38 groups selected independently. 7 -. 7 - The compound according to claim 1, further characterized in that D is a 5-membered heteroaromatic ring system, substituted by 1 or 2 independently selected R38 groups. 8. The compound according to claim 1, further characterized in that D is phenyl, pyridyl, imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or 2 independently selected R38 groups. 9. The compound according to claim 1, further characterized in that each R38 is independently selected from the group consisting of dC6 alkyl, - (CH2) jNR39 (CH2) j (CH) (NH2) (COOH), - (CH2) ) jNR39 (CH2) jCOOH, (CH2) jNR39 (CH2) nR36 and -C0-C6alkyl- (optionally substituted heterocycle). 10. - The compound according to claim 1, further characterized in that R39 is selected from the group consisting of H, -C (0) -C C6 alkyl, -C (O) 0-C-C6alkyl, -C (0) -CrC6alk L-NH2, -S02-Me, -C (O) (CH2) 0-4O (CH2) 1-4OC1-C6alkyl and -C (O) CH [CH (C1-C6alkyl) 2] NR3R3 11. - The compound according to claim 1, further characterized in that R36 is -OMe. 12. - The compound according to claim 1, further characterized in that R99 is -OMe. 13. - The compound according to claim 1, further characterized in that M is where * represents the point of attachment to D, and † represents the point of attachment to Z. 14. The compound according to claim 1, further characterized in that Ar is selected from the group consisting of phenyl, pyrazine, pyridazine, pyrimidine and pyridine, wherein each of said phenyl, pyrazine, pyridazine, pyrimidine and pyridine is optionally substituted by 0 to 4 groups R2. 15. - The compound according to claim 1, further characterized in that G is selected from the group consisting of R13 R13 13 R 13 R 13 Q O o o O 0 16 -. 16 - The compound according to claim 1, further characterized in that G is selected from the group consisting of 17. - The compound according to claim 1, further characterized in that Q is selected from the group consisting of phenyl, cyclopropyl, isoxazolyl, cyclohexyl, thiazolyl, tetrahydrofuran, pyrazolyl, cyclobutyl and cyclopentyl, optionally substituted with between zero and two R20. 18. - The compound according to claim 1, further characterized because each R20 is independently selected between the group consisting of -P (= 0) (Me) 2, methyl, halo, trihalomethyl, methoxy, - C (0) NH2, heteroaryl, COOH, -S02NH2, -C (0) NH2, COOMe-, -C (0) N (H) (Me), -C (0) N (Me) 2 and -S02Me. 19 -. 19 - The compound according to claim 1, further characterized in that D is phenyl, pyridyl, imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or 2 independently selected R38 groups; Month Z is -O-; Ar is phenyl optionally substituted by 0 to 4 halo; and G is selected from the group formed by R13 R 13 R 13 R13 R13 Q o o o o wherein Q is optionally substituted with from 0 to 4 R20 selected independently. twenty - . 20 - The compound according to claim 1, further characterized in that D is pyridyl substituted with (CH2) jNR39 (CH2) nR35, - (CH2) jNR39 (CH2) [0 (CH2),] x (CH2) jR99, -C0-C6alkyl- (heterocycle optionally substituted with an oxo), - (CH2) jNR39 (CH2) jCOOH, - (CH2) jNR39CH (CH3) (CH2) jR99 or - (CH2) iNR39 (CH2) j (CH) (NH2) (COOH); Month Z is -0-; Ar is phenyl optionally substituted by an F, and G is R13 wherein Q is optionally substituted with 0 to 4 R selected independently. 21. The compound according to claim 1, characterized in that D is pyridyl substituted with - (CH2) jNR39 (CH2) nR36, - (CH2) jNR39 (CH2) ¡[0 (CH2) ¡] x (CH2) iR99, - C0-C6alkyl- (heterocycle substituted with oxo), - (CH2) jNR39 (CH2) jCOOH or - (CH2) jNR39 (CH2) j (CH) (NH2) (COOH); R "is OMe; M is Z is -0-; Ar is phenyl optionally substituted by an F, and G is where R13 is H; and Q is phenyl optionally substituted with 1 or 2 R20 selected independently, wherein each R20 is independently selected from the group consisting of -P (= 0) (Me) 2, methyl, halo (eg, F), trihalomethyl , methoxy, -C (0) NH2, heteroaryl, -COOH, -S02HN2, -C (0) NH2, -COOMe, -C (0) N (H) (Me), -C (0) N (Me) 2 and -S02Me or Q is pyrazolyl optionally substituted with methyl, or Q is cyclopropyl, cyclobutyl or tetrahydrofuran, or Q is isoxazolyl substituted with methyl. 22. The compound according to claim 1, further characterized in that D is imidazolyl substituted with a C Cealkyl and a - (CH 2) j NR 39 (CH 2) j R 36 M is Z is -O-; Ar is phenyl optionally substituted with an F, and G is where Q is optionally substituted with 0 to 4 selected R independently. 23. The compound according to claim 1, further characterized in that D is imidazolyl substituted with a Ci-C6alkyl and a - (CH2) jNR39 (CH2) nR36; Month Z is -O-; Ar is phenyl optionally substituted with an F, and G is where R13 is H, and Q is phenyl optionally substituted with 0 to 4 R20 independently selected. 24. - The compound according to claim 1, further characterized in that D is imidazolyl substituted with a Ci-C6alkyl 36. and a - (CH2) jNRJ9 (CH2) nRJO; is Z is -O-; Ar is phenyl optionally substituted with an F and G is wherein R 13 is H, and Q is phenyl optionally substituted with one or two groups independently selected from the group consisting of -P (0) Me 2, methyl, F, trifluoromethyl, methoxy, -C (0) NH 2 and oxazolyl, or Q is cyclopropyl. 25. The compound according to claim 1, further characterized in that D is pyridyl substituted with (CH2) jNR39 (CH2) nR36, - (CH2) jNR39 (CH2) i [O (CH2) i] x (CH2) jR "1 -C0-C6alkyl- (heterocycle substituted with an oxo), - (CH2) jNR39 (CH2) jCOOH or - (CH2) jNR39 (CH2) j (CH) (NH2) (COOH); R99 is OMe; M is Z is -O-; Ar is phenyl optionally substituted with an F, and G is where R 3 is H; and Q is cyclopropyl. 26. The compound according to claim 1, further characterized in that D is pyridyl substituted with -C0-C6alkyl- (optionally substituted heterocycle); Month Z is -O-; Ar is phenyl optionally substituted with an F, and G is R13 R13 where R13 is H; and Q is cyclopropyl. 27. The compound according to claim 1, further characterized in that D is pyridyl substituted with -CH 2 - (5- or 6-membered heterocyclyl) wherein the 5- or 6-membered heterocyclyl is substituted with 0, 1 or 2 oxo); Month Z is -O-; Ar is phenyl substituted with an F, and G is R13 R13 O o wherein R13 is H, and Q is cyclopropyl. 28. - The compound according to claim 1, further characterized in that D is pyridyl substituted with Month Z is -O-; Ar is phenyl substituted with an F, and G is R13 R13 I i 0 or where R13 is H; and Q is cyclopropyl. 29. The compound according to claim 1, further characterized in that D is pyridyl substituted with - (CH 2) j NR 39 (CH 2) - [0 (CH 2) 1] x (CH 2) j R 99; R99 is OMe; Month Z is -O-; Ar is phenyl substituted with an F, and G is R13 R13 wherein R13 is H; and Q is cyclopropyl. 30. - A composition comprising a compound of any of claims 1 to 29. 31- An in vitro method for inhibiting kinase activity, the method comprising contacting kinase with a compound of any of claims 1 to 29 or a composition thereof. 32. The use of a compound of any of claims 1 to 29 or a composition thereof in the manufacture of a medicament for inhibiting angiogenesis in a patient. 33. The use of a compound of any one of claims 1 to 29 or a composition thereof in the manufacture of a medicament for treating a disease sensitive to inhibition of kinase activity in a patient. 34. The use of a compound of any of claims 1 to 29 or a composition thereof in the manufacture of a medicament for treating a cell proliferative disease in a patient. 35. The use of a compound of any one of claims 1 to 29 or a composition thereof in the manufacture of a medicament for treating an ophthalmic disease, condition or disorder in a patient.
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